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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

LEUKEMIA((LEUKAEMIA))

DEFINITION:

Leukemia is a cancer of the blood cells, most generally white blood cells (WBCs). In leukemia, the WBCs have mutated and may divide too quickly, eventually crowding out normal functioning red and white blood cells.

TYPES OF LEUKEMIA:

There are several different types of leukemia. In general, leukemia is grouped by how fast it gets worse and what kind of white blood cell it affects.

A. It may be acute or chronic. Acute leukemia gets worse very fast and may make patient feel sick right away. Chronic leukemia gets worse slowly and may not cause symptoms for years.

B. It may be lymphocytic or myelogenous. Lymphocytic (or lymphoblastic) leukemia affects white blood cells called lymphocytes. Myelogenous leukemia affects the other type of cells that normally become granulocytes, red blood cells, or platelets.

There are four main types of leukemia:

Acute myeloblastic leukemia (AML) Chronic myelocytic leukemia (CML) Acute lymphoblasti leukemia (ALL) Chronic lymphocytic leukemia (CLL)

Acute myeloid leukemia( AML ):

Also known as acute myelogenous leukemia, acute myeloblastic leukemia, acute granulocytic leukemia or acute nonlymphocytic leukemia, is a fast-growing form of cancer of the blood and bone marrow.

AML is the most common type of acute leukemia. It occurs when the bone marrow begins to make blasts, cells that have not yet completely matured. These blasts normally develop into white blood cells. However, in AML, these cells do not develop and are unable to ward off infections.

In AML, the bone marrow may also make abnormal red blood cells and platelets. The number of these abnormal cells increases rapidly, and the abnormal (leukemia) cells begin to crowd out the normal white blood cells, red blood cells and platelets that the body needs.

Due to their immaturity, they are unable to function properly to prevent or fight infection. Inadequate numbers of red cells and platelets being made by the marrow cause anaemia, and easy bleeding and/or bruising

One of the main things that differentiates AML from the other main forms of leukemia is that it has eight different subtypes, which are based on the cell that the leukemia developed from. The types of acute myelogenous leukemia include:

Myeloblastic (M0) - on special analysis Myeloblastic (M1) - without maturation Myeloblastic (M2) - with maturation Promyeloctic (M3) Myelomonocytic (M4)

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

Monocytic (M5) Erythroleukemia (M6) Megakaryocytic (M7)

CHARACTERISTC FEATURES OF ACUTE LEUKEMIA:

-The condition progresses rapidly and aggressively, requiring immediate treatment.

-The site of the disease is bone marrow where all the cell lines may be depressed .

-Bone marrow aspiration is mandatory for diagnosis (˃ 20% blasts ).

-There is no enough time for the organs to be hugely enlarged (( may be palpable )).

-The blood is circulating and malignant cells may invade the organs.

-There is no surgical treatment for it.

INCIDENCE:

Acute leukaemia is an uncommon type of cancer.

About 7,600 people are diagnosed with leukaemia each year in the UK.

AML is an uncommon type of cancer. Around 2,600 people are diagnosed with the condition each

year in the UK.

AML can develop at any age, but it's more common in people over the age of 60.

SYMPTOMS:

Many people often do not experience symptoms in the early stages of certain types of leukemia, or the symptoms develop slowly. Acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) progress much faster and symptoms may worsen more quickly than with the chronic leukemias (CML and CLL).

Some leukemia symptoms, like night sweats, fever, fatigue and achiness, often resemble flu-like symptoms. If you have the flu, symptoms will likely subside as you get better. Make an appointment to see your doctor if the symptoms persist longer than expected.

Some general symptoms of leukemia include: Fever, chills Fatigue, weakness Loss of appetite, weight loss Night sweats Bone/joint pain Abdominal discomfort Headaches Shortness of breath Frequent infections Easy bruising or bleeding Petechiae (small red spots under the skin)

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

AML symptoms:

Bone marrow depression—anemia , bleeding , infection

Bony pain with sternal tenderness

DIC , gum hyperatrophy

S&S:

1. ANEMIA :

Pallor

Easy fatigability

Dyspnea on mild exertion

Lassitude

Syncopal attacks

Headache

Palpitation

Anorexia

Taste disturbance

Tinnitus

Dizziness

Dimension of vision

Insomnia

Angina

Parasthesia in fingers and toes

2. BLEEDING (( THROMBOCYTOPENIA)):

Petechiae

Bruisability

Epistaxis

Gingival bleeding (spongy bleeding)

Melena

Hematuria

Purpura

Spontaneous involving ---CNS , LUNG , GIT MUCOUS MEMBRANE

Haemorrhage increased ˂ 20 x 10000/ml

3. INFECTION:

Is inversely related to number of circulating neutrophils

Major risk in patient with granulocyte ˂ 0.5 x 10000/ml

Neutrophil may function abnormally and comprises host defenses.

The leukemia and its treatment cause a breakdown of mucosal barrier & systemic infections

usually develop from skin, throat, GIT.

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

In leukocytosis, increase in blast cells of ˃ 100 x 10 000 /ml leads to leukostasis due to

occlusion of the microcirculation by blast cells leading to hypoperfusion of lung and brain.

Common sites of infections:

Skin; Gingival; Ulcers in mouth and pharynx ;Perirectal tissues ;Lung;Urinary tract;

Sore throat

Septicemia usually occurs without an apparent cause.

4. HEPATOMEGALLY AND SPLENOMEGALLY:

Rare in AML.

The visceral involvement can produce symptoms of nausea , abdominal fullness and satiety.

Lymphoadenopathy –AML 50%

Practical point—extramedullary leukemia can precede detectable involvement of B.M.

5. EXTRAMEDULLARY TISSUES :

Acute leukemia may infiltrate –skin, lung, eye, kidney ,nasopharynx

CHLOROMAS----soft tissues masses of leukemic cells.

6. SYMPTOMS RELATED TO THE EXPANDING MALIGNANT CELL MASS:

Bony pain and sternal tenderness

This occur in half of patients

Osteolytic lesions are rare

Renal abnormalities due to :

A. Leukemic infiltration

B. Ureteral obstruction by urate nephropathy—enlarged LN, uric acid stone, infections

,haemorrhage.

GIT----bleeding, distention ,satiety ,constipation((due to organomegally or leukemic

infiltrate)) .

7. METABOLIC DISTURBANCE :

Hypokalemia and hyponatremia due to renal involvement .

LDH—lactic dehydrogenase may be increased.

CLASSIFICATION OF ACUTE LEUKEMIA:

Classification of acute leukemias used to rely entirely on morphology and histochemical changes, but

now information regarding cytogenetic patterns and correlations with immunophenotype, oncogene

expression, and gene mutation has changed the biology of this disease

1. FAB classification(French-American-British) :1970 A classification of acute leukemia produced by a three-nation joint collaboration. A schema that divides acute leukemias into lymphoid–ALL or myeloid–AML cell lines

This is based on the study of microscopic features and cytochemistry of blast cells. Acute myelogenous leukemia is subdivided into eight types(M0-M7) based on the type of cell from which

the leukemia developed and how mature the cells are.

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

Acute myeloid leukemia (AML)

Subtypes M0 through M5 all start in precursors of white blood cells. M6 AML starts in very early forms of red blood cells, while M7 AML starts in early forms of cells that make platelets. M1 Myeloblasts without maturation M2 Myeloblasts with maturation (best AML prognosis) M3 Hypergranular promyelocytic leukemia (faggot cells) M3V Variant, microgranular promyelocytic leukemia M4 Myelomonocytic leukocytes M5 Monocytic, subtype

a. Poorly differentiated monocytic leukemia b. Well differentiated monocytic leukemia M6 Erythroleukemia/DiGuglielmo syndrome M7 Megakaryocytic leukemia Pleomorphic undifferentiated cells with cytoplasmic blebs; myelofibrosis or ↑ BM

reticulin; positive for platelet peroxidase antifactor VIII

2. World Health Organization (WHO) classification of AML

The FAB classification system is useful and is still commonly used to group AML into subtypes. But it doesn’t take into

account many of the factors that are known to impact prognosis (outlook). In 2001, the World Health Organization (WHO)

published a newer system that includes some of these factors to try to help better classify cases of AML based on a

patient’s outlook.

The WHO classification system divides AML into several broad groups:

1. AML with certain genetic abnormalities

AML with a translocation between chromosomes 8 and 21

AML with a translocation or inversion in chromosome 16

AML with changes in chromosome 11

APL (M3), which usually has translocation between chromosomes 15 and 17

2. AML with multilineage dysplasia (more than one abnormal myeloid cell type is involved)

3. AML related to previous chemotherapy or radiation

4. AML not otherwise specified (includes cases of AML that don’t fall into one of the above groups; similar to the

FAB classification)

Undifferentiated AML (M0)

AML with minimal maturation (M1)

AML with maturation (M2)

Acute myelomonocytic leukemia (M4)

Acute monocytic leukemia (M5)

Acute erythroid leukemia (M6)

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

Acute megakaryoblastic leukemia (M7)

Acute basophilic leukemia

Acute panmyelosis with fibrosis

Myeloid sarcoma (also known as granulocytic sarcoma or chloroma)

5. Undifferentiated or biphenotypic acute leukemias (leukemias that have both lymphocytic and myeloid features).

Sometimes called ALL with myeloid markers, AML with lymphoid markers, or mixed lineage leukemias.

Morphological subtypes of AML: AML occurs more often in men and is usually diagnosed in

individuals over 50, although it can occur at any age.

M1

((AML without maturation)) 20% of AML

Myeloblast predominant

Distinct nucleoli

Few Auer rods , Azurophilic granules

( > 90% type I and II blasts ) of marrow nonerythroid cells is present. Most of the blasts are agranular. Auer rods are infrequent.

Staining: Relatively few blasts (5-10%) are MPO (myeloperoxidase) positive. A minimum of 3% MPO positive blasts are required for diagnosis. NSE and PAS are generally negative.

Immunophenotype: Variably positive for CD13, CD14, CD11b, CD33, and HLA-DR.

Chromosome Abnormalities: t(9;22) Philadelphia

chromosome, 8+, -5, and -7.

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

M2 AML with maturation ((acute myeloblastic with maturation))

The most common (20-40%) type of AML

Maturation: Type II blasts ((Myeloblast)) are common and Auer rods are frequent (promyelocytes-

myelocytes).

Positive to peroxidase sudan black

Staining: The blasts are largely MPO peroxidase sudan black positive. NSE and PAS are generally

negative.

Immunophenotype: Variable positivity for CD13, CD33, and HLA-DR, but are -ve for CD14 and CD11b.

Chromosome Abnormalities: t(8;21), 8+, -5, and -7.

Cell Morphology: In some cases the immature cells have abundant, frequently basophilic cytoplasm, with variable numbers of often indistinct, sometimes coalescent granules. If such immature cells are < 10% the diagnosis is M1, but if > 10% the diagnosis becomes M2.

M3

o Acute Promyelocytic Leukemia (APL)

Maturation: the majority of promyelocytes are hypergranular. Auer rods are frequent and often multiple.

Staining: The cells are MPO and chloroacetate esterase (CAE) positive, but generally negative for NSE (NSE positive in 25%).

Immunophenotype: Positivity for CD13 and CD33, but are usually negative for HLA-DR.

Chromosome Abnormalities: The t(15;17) is unique to promyelocytic leukemia.

DIC is seen in M3 by thromboplastic material released by leukemic cells & exacerbated by chemotherapy.

Treatment Options: Why is it critical to distinguish M3 from other myeloid leukemias?

The t(15;17) splits the retinoic acid receptor (RAR) alpha-gene on 17. This is replaced by the myl gene from 15, producing a novel protein: myl/RAR-a. Myl/RAR-alpha may suppress the normal RAR-aalpha allele thus blocking expression of retinoic acid genes needed for myeloid differentiation.

Recognition of M3 leukemias is critical because M3s can be initially treated with retinoic acid rather than toxic chemotherapy.

Microgranular Variant:

In the microgranular variant, M3v, the leukemic cells have a

monocytic appearance with clefted angel-wing nuclei and

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

abundant cytoplasm having at best indistinct cytoplasmic granulation.

The cytochemical, immunophenotypic and chromosomal features are indentical to the classic M3.

Both forms of acute promyelocytic leukemia are associated with a high incidence of disseminated intravascular coagulation (DIC) and hemorrhage.

M4

Acute Myelomonocytic Leukemia (AMML) – ((30%))

Maturation: Differentiation along both myeloid and monocytic lines. Monocytes and promonocytes represent > 20%, but < 80% of the marrow differential.

Staining: More than 20% of the blasts should be MPO + and more than 20% should be NSE + .

Diagnosis Aides:

I. High serum lysozyme (3x normal)

II. A peripheral monocytosis of > 5x10

/L in an otherwise M2 marrow and increased lysozyme

III. A peripheral monocytosis of >5 x10

/L in M2 marrow and >20% NSE + marrow blasts.

Chromosome Abnormalities: t(4;11), t(9;11), 8+ and -7.

Variant: M4e variant in which eosinophils (> 5%) are increased in number and abnormal associated with abnormalities of chromosome 16.

Staining of Variant: CAE, usually negative in eosinophils, is frequently positive in the abnormal eosinophils of M4e.

M5

o Acute Monocytic Leukemia (AMoL) – ((10%))

o Differentiatiation: Monocytic------Two subtypes:

1. M5a is the poorly differentiated form

2. M5b is the well-differentiated form

o Chromosome Abnormalities: t(9;11), 8+, -5, and -7. Chromosome abnormalities of 11q are closely associated with M5a

o Cell Morphology: Note the nuclear folds and the relatively large nucleoli typical of monoblasts at right.

Monoblast Myeloblasts

fewer granules more granules

occasionally will see slight nuclear fold typically round nucleus

few, large nucleoli more nucleoli

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

M5a

This is the M5a or poorly differentiated form of acute monoblastic leukemia. >80% of cells are monoblasts.

Staining: The blasts in M5a are generally MPO negative, but strongly positive for the nonspecific esterase (NSE) and inhibited by Fluoride.

M5b

This is the M5b or differentiated form of acute monoblastic leukemia in which > 80% of the leukemic cells are monoblasts, promonocytes, and monocytes. Note the large nucleoli so typical of monoblasts

Staining: The blasts of M5b usually contain some peroxidase activity and, of course, are positive for nonspecific esterase (NSE) and inhibited by Fluoride.

M4 & M5 have extramedullary involvement of skin ,gingival and CNS.

M6

o Acute Erythroblastic Leukemia

Maturation: Erythroleukemia is rare and difficult to diagnose. More than 50%* of the nucleated marrow cells are abnormal nucleated red blood cells.

Morphology: The leukemic red cells are frequently bizarre with extreme dysplastic features including: giant forms, multinucleation, cytoplasmic vacuolization, cytoplasmic buds, and megaloblastoid changes.

30% considered adequate by some

Staining: The blasts are MPO negative, but often positive for NSE. The malignant red cells are PAS positive, (forming PAS positive lakes or containing coarse chunks of PAS positive material).

Immunophenotype: Positive for glycophorin A.

Chromosome Abnormalities: 8+, -5, del(5q), and -7.

Differential Diagnosis:

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

1. Congenital dyserythropoietic anemia

2. Myelodysplastic syndrome

3. Sideroblastic anemia

4. Megaloblastic anemia.

M7

Acute Megakaryocytic Leukemia (AMKL) – ((5%))

M7 blasts are often resemble lymphoblasts, although M7 leukemias may be accompanied by atypical megakaryocytes. The marrow is often fibrotic.

Morphology:

M7 blasts may have granular cytoplasm and shed 'platelets'.

M7 blasts often clump together

Immunoperoxidase staining (brown) for Factor VIII related protein identifies the blasts as being of megakaryocyte lineage

Staining: M7 blasts are MPO negative and variably positive for PAS and NSE.

Diagnosis: Determination of an M7 subtype is dependent on immunologic evidence or electron microscopic ultracytochemical identification of platelet peroxidase (PPO).

Immunophenotypic studies of M7 are positive for glycoproteins GP Ib andGP IIb/IIIa.

Factor VIII related protein is usually found in the megakaryoblast cytoplasm.

Chromosome Abnormalities: t(1;22), have been associated with M7 in infants.

Myeloid Leukemia with Minimal Differentiation - FAB M0:

M0 is a recently defined FAB nonlymphoid leukemia dependent on the immunologic identification of myeloid antigens. Morphologic and cytochemical studies show no distinguishing features.

Staining: M0 blasts are nondescript (no Auer rods) and are MPO, PAS and NSE negative (<3%).

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

Electron microscopic ultra cytochemical studies for platelet peroxidase are negative.

Immunophenotype: M0 blasts are negative for B and T lymphoid antigens, platelet glycoproteins GP Ib and GP IIb/IIIa, and erythroid glycophorin A. Myeloid antigens such as CD13, CD33 and CD11b are variably positive. CD34 and HLA-DR are generally positive.

Chromosome Abnormalities: No particular association.

ADDITIONAL INFORMATION REGARDING LEUKEMIA:

Eosinophilic leukemia is a rare variant of acute myeloid leukemia in which blasts and immature eosinophils proliferate. CNS involvement appears to be common. Should be distinguished from CML with large numbers of eosinophils.

Basophilic leukemia is a rare subset of AML associated with t(6;9) and abnormal 12p. Ultrastructural studies of the immature basophilic granules may be necessary. Philadelphia chromosome positive cases may be related to the blast crisis of CML

Blast crisis of chronic leukemia refers to a phase of a chronic leukemia resembling an acute leukemia ( in which blasts are >30%). In chronic myelogenous leukemia (CML), blast crisis signals the terminal phase of the disease for which there is no effective therapy.

Secondary (therapy-induced) acute leukemia is nearly always myeloid and is usually preceeded by a myelodysplastic syndrome involving all three hematopoietic cell lines (panmyeloisis).

Abnormalities of chromosomes 5, 7, and 11 are common in therapy-induced leukemias.

This is most common after alkylating chemotherapy or radiation therapy, with an average latent period of 5 years (range1-15 years).

Hypocellular acute leukemia is a situation in which the marrow cellularity (< 30%) often resembles aplastic anemia, but with numerous (>30%) blasts in the interstitium of the marrow. About 5-10% of acute myeloid leukemias present in this form.

Extramedullary myeloid cell tumor (EMCT) or granulocytic sarcoma or chloroma is an extramedullary tissue mass of blasts and immature myeloid cells. The surface of a freshly cut EMCT turns light green (hence the name chloroma) upon exposure to air as large amounts of peroxidase are oxidized. EMCT may represent the initial manifestation of acute leukemia or signal relapse. The blast crisis of chronic myeloid leukemia may present as EMCT. Masses of monoblasts as may be seen in M5 leukemias are also sometimes referred to as EMCT.

The surface of this subcutaneous chloroma turned pale green after exposure to air. The patient had been in remission following Rx for AML.

Acute biphenotypic leukemia –

Cells contain both markers (lymphoid and myeloid)

It is a leukemia of primitive pleuripotent stem cells.

To differentiate ALL from AML ( M1 from L2 ):

1. Cytochemical stains

2. Analysis of myeloid and lymphoid antigen

3. Electron microscopy to detect promyelocytic granules

Leukemia in BM can’t be detected when cell mass ˂1000/ml

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

Clinical criteria of complete remission:

1. ˂5% blast cells in the BM with absence of leukemic cells in peripheral blood

2. The restoration of normal peripheral blood count

3. The absence of physical findings attributable to extramedullary involvement leukemia

THE SUMMARY SHEET OF AML FAB:

Morphological Features of AML

TYPE(FAB) CHARACTERISTIC MORPHOLOGY

Acute myelocytic leukemia (M1)

Cells very undifferentiated, occasionally cytoplasmic granules, some promyelocytes seen.

Acute myelocytic leukemia (M2)

Granulated blasts predominate, small number of monocytoid cells may be present, differentiation beyond promyelocytic stage evident, +/- Aeur bodies

Acute promyelocytic leukemia (M3)

Typically, hypergranular promyelocytes predominate, cells have large basophilic and esoinophilic granules, +/- Auder bodies

Acute myelomonocytic leukemia (M4)

Monocytic and granulocytic precursors seen, serum lysozyme elevated, +/- Auer bodies

Acute monoblastic leukemia (M5)

Large monoblasts with abundant, agranular cytoplasm that may be vacuolated and basophilic

Erythroleukemia (M6) Megaloblastoid red cell precursors predominate, myeloid blasts also seen, multinucleated red cell precursors common

Megakaryocytic leukemia (M7)

Variable morphology, megakaryocytic features may not be seen with light microscopy

Identification of AML subtypes is important because several new drugs have more activity against some varieties than against others.

Prognosis and some clinical features may differ considerably among the various AML subtypes.

Histochemical Features of AML

FAB HISTOCHEMISTRY

M1 Occasional peroxidate+ granules, PAS-

M2 Strongly peroxidase+, PAS-

M3 Strongly peroxidase+, PAS-

M4 Strongly peroxidase+, some cells may be PAS+

M5 Many be peroxidase+ and PAS+, nonspecific esterase stains are strongly + and inhibited by NAF

M6 Red cell precursors are PAS+, ringed sideroblasts are seen with iron stains

M7 Variable, platelet peroxidase can be demonstrated by electron microscopy

Distinction among the various subgroups of AML is now possible with greater precision because of new histochemical studies and immunologic techniques.

Immunophenotyping and terminal deoxytransferase (TDT) determination may help distinguish between AML and ALL, and between the various subtypes of AML.

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

AML MARKERS

Morphologic ----------Auer bodies AND "malignant" primary granules

Cytoplasmic organelles

o chloracetate esterase

o Sudan B

o myeloperoxidase

Cytogenetic

o t(8;21)

o t(15;17)

o -5,-7

Immunologic/biochemical

o lysozyme

o cell surface markers

QUESTIONS FOR TRAINING: 1. A 12-year-old girl is noted to be pale and lethragic by her parents. You note some petechiae

on her legs. A chest roentgenogram is normal. There is no lymphadenopathy. A CBC revealed a WBC of 25.0 x10 /L with 15% blasts.The bone marrow aspirate differential count included 32% type I blasts; 13% type II blasts; 10% type III blasts; 10% promyelocytes; 25% myelocytes; 3% PMNs and 7% monocytes. Many of the blasts contained Auer rods. There were fewer than 50% erythroblasts.

With the results of this information you make the following diagnosis:

A. Acute myelocytic leukemia, M1

B. Acute myelocytic leukemia, M2

C. Acute promyelocytic leukemia, M3

D. Acute myelocytic leukemia, M4

E. Acute myelocytic leukemia, M5

ANSWER

In this case >30% blasts and >10% cells with maturation ( promyelocytes - polymorphonuclear leukocytes) are seen. Type II blasts are common and Auer rods are frequently, all features of acute myelocytic leukemia with maturation - M2. Too much maturation (too many Type III blasts, promyelocytes and myelocytes) for an M1

Fewer than 20% were monocytic cells, thus not an M4 or M5.

2. A 25-year-old woman comes to you because of a severe headache and epistaxis. She is pale

and has petechiae on her arms and chest. There is no lymphadenopathy or hepatosplenomegaly. A chest roentgenogram is normal. The WBC was 18.0 x10 /L with 10% blasts. On the bone marrow aspirate it was difficult to distinguish between Type II and III blasts and promyelocytes. There were an estimated15% type I blasts and 75% immature cells (type II and type III blasts and promyelocytes). The remainder were dysplastic myelocytes. There were fewer than 50% erythroblasts. Cytogenetic studies showed a t(15;17) chromosome abnormality.

With the results of this information you make the following diagnosis:

A. Acute myelocytic leukemia, M1

B. Acute myelocytic leukemia, M2

C. Acute promyelocytic leukemia, M3

D. Acute myelocytic leukemia, M4

E. Acute myelocytic leukemia, M5

ANSWER

Because of the difficulty of distinguishing between Type II and III blasts and promyelocytes (75% type II and type III blasts and promyelocytes) the differential is between an FAB M2 and an FAB M3 myeloid leukemia. The key is the cytogenetic study showing a t(15;17) chromosome abnormality which is diagnositic of promyelocytic leukemia (FAB-M3).

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

3. A 45-year-old woman is referred to you from her dentist because of swollen and bleeding

gums. Her conjunctiva were pale and she had been feeling exceptionally wornout. There is mild splenomegaly. A chest roentgenogram is normal. The WBC was 23.0 x10 /L with 44% blasts. The bone marrow aspirate showed > 55% large blasts with folded nuclei and large nucleoli. The remainder were promonocytes, monocytes and a few dysplastic myelocytes. There were fewer than 50% erythroblasts. Cytogenetic studies showed a t(9;11) chromosome abnormality.

With the results of this information you make the following diagnosis:

A. Acute myelocytic leukemia, M1

B. Acute myelocytic leukemia, M2

C. Acute promyelocytic leukemia, M3

D. Acute myelomonocytic leukemia, M4

E. Acute monocytic leukemia, M5

ANSWER

The finding of > 55% large blasts with folded nuclei and large nucleoli accompanied by numerous promonocytes, monocytes and a few dysplastic myelocytes indicates a monoblastic leukemia. An M4 might also be considered as monocytes are part of the M4 milieu.

Key is the cytogenetic study showing a t(9;11) chromosome abnormality which is closely associated with acute monocytic leukemia (FAB M5).

4. A 37-year-old man comes to you complaining of fatigue and increasing SOB, and now a fever (the fever is what got him to see you). He has had to stop jogging. He is pale and diaphoretic. There is no lymphadenopathy or hepatosplenomegaly. A chest roentgenogram is shows dense bilateral infiltrates c/w pneumonia. The WBC is 78.0 x10 /L with 20% blasts. On the bone marrow aspirate there were an estimated 25% type I blasts and 55% immature cells (type II and type III blasts and promyelocytes). The remainder were dysplastic myelocytes.Cytogenetic studies showed a t(8;21) chromosome abnormality.

With the results of this information you make the following diagnosis:

A. Acute myelocytic leukemia, M1

B. Acute myelocytic leukemia, M2

C. Acute promyelocytic leukemia, M3

D. Acute myelocytic leukemia, M4

E. Acute lymphoblastic leukemia

ANSWER

The difficulty of distinguishing among type II blasts, type III blasts and promyelocytes can make the morphologic distinction between an M2 and an M3 (and possibly an M4) leukemia difficult.

The finding of a t(8;21) chromosome abnormality is of great help in classifying this leukemia, a t(8;21) abnormality is associated with acute myelocytic leukemia with differentiation. Other chromosome abnormalities commonly associated with M2 AMLs are 8+, -5, and -7.

5. A 32-year-old man comes to you because of a persistent cough x3 weeks and noted some shortness of breath. He is pale and has several ecchymoses and petechiae on his back and legs. He has several small axillary nodes and an ill-defined mediastinal mass. The WBC is 114.0 x10 /L with 90% blasts. The marrow aspirate showed 54% blasts; 8% promyelocytes; 15% myelocytes; 3% bands;12% segmented neutrophils; 5% eosinophils, and 3% basophils. The blasts are negative for myeloperoxidase; nonspecific esterase and PAS. Chromosome studies showed a t(10;14)(q24;q11) abnormality. Immunologic marker studies are pending.

With the results of this information you make the following diagnosis:

A. Acute myelocytic leukemia, M1

B. Acute myelocytic leukemia, M2

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

C. Acute promyelocytic leukemia, M3

D. Acute myelocytic leukemia, M4

E. Acute lymphoblastic leukemia

ANSWER

A 32-year-old man comes to you because of a persistent cough x3 weeks and noted some shortness of breath. He is pale and has several ecchymoses and petechiae on his back and legs.

The ill-defined mediastinal mass and the high peripheral blood blast count > 100 x10 /L is typical of acute lymphoblastic leukemia of T-cell type. The nonmyeloid nature of the blasts is indicated by the negative myeloperoxidase, nonspecific esterase and PAS.

The chromosome studies showing a t(10;14)(q24;q11) abnormality is further evidence of the T-lymphoblastic nature of this lesion.

AML ----

THE PRESENCE OF AUER RODS DIAGNOSTIC-----BY Romanorsky dye and cytochemical stains MORE COMMON IN ADULT POLYCLONAL SEVER BLEEDING MAY OCCUR

Cytogenatic studies -----the most powerful prognostic factor Favorable in AML---t(8 , 21) , t(15 , 17) , inv 169 Favorable in ALL --- Hyperlipoid state

Risk Factors for Acute Myeloid Leukemia

If something increases your risk of getting a disease, it's called a risk factor. Risk factors don't tell the whole

story. For example, you can have few risk factors and still get a disease or have several and not get it.

Acute myeloid leukemia risk factors include:

1. Smoking

2. Exposure to certain chemicals such as benzene , certain cleaning products, detergents, and paint

strippers.

3. Treatment with certain chemotherapy drugs used to treat other cancers, such

as mechlorethamine, procarbazine, and chlorambucil -- especially when combined

with radiation therapy

4. Exposure to high doses of radiation

5. Certain blood disorders, such as myeloproliferative disorders (for example, chronic myelogenous

leukemia)

6. Certain congenital syndromes, such as Down syndrome

7. Being male

8. For most people, the cause of AML is unknown. There is not a way to prevent it, but you may reduce

your risk by quitting smoking and avoiding exposure to chemicals.

Diagnostically Important AML Markers

Morphologic o Auer bodies o "malignant" primary granules

Cytoplasmic organelles o chloracetate esterase o Sudan B

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

o myeloperoxidase

Cytogenetic o t(8;21) o t(15;17) o -5,-7

Immunologic/biochemical o lysozyme o cell surface markers

A variety of morphologic, cytoplasmic, cytochemical, and biochemical features are associated with AML that can aid in diagnosis.

No available marker is either totally specific or sensitive enough to be used in all cases.

Cytogenetic analyses should be performed at diagnosis in all patients with AML. Approximately 65% of patients will have abnormal karyotypes.

Cytogenetic abnormalities may help determine prognosis

Work-Up for Patient with AML:

Complete history:

o family, work, and medical history ---radiation and chemical exposure history

Complete physical examination, with special attention to:

o Temperature, Iymph node-bearing areas and splenic area, optic fundi and cranial nerves

o Potential sites of infection:

Skin , including axillae

Oropharynx , including gingivae

Lungs

Perianal area

o Peripheral blood studies:

Hematocrit , leukocyte count, platelet count

Leukocyte differential count

o Bone marrow examination:

Perform biopsy to determine cellularity

Aspirate smears stained with Wright's, Sudan black, and esterase stains; periodic acid-Schiff reagent; iron stain; and immunofluorescent stain for terminal transferase

Aspirate for karyotyping and immunophenotyping

Blood chemistries and other studies:

Serum electrolytes, uric acid, blood urea nitrogen, and muramidase (lysozyme)

Coagulation profile, including fibrinogen level, prothrombin time, and partial thromboplastin time

Liver function analysis

Chest radiographs:

chest posteroanterior and lateral radiographic films

Transfusion work-up:

determine blood type and human leulocyte antigen type if patient has circulating lymphocytes

do same for family members who are willing to serve as platelet, granulocyte, or potential marrow donors

Peripheral Blood Features of AML

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

The peripheral white blood cell count may be increased, decreased, or normal with approximately equal frequency.

Granulocytopenia is very common. Approximately 1/2 of all patients will have granulocyte counts < 1,000/uL.

Thrombocytopenia is frequently observed and platelet counts <20,000/uL are common.

The hematocrit is generally low but severe anemia is uncommon.

Circulating blast cells are absent from the peripheral blood in approximately 15% of AML patients initially, and in 1/2 of patients presenting with leukopenia

Certain factors affect prognosis (chance of recovery) and treatment options:

The prognosis (chance of recovery) and treatment options depend on:

The age of the patient.

The subtype of AML.

Whether the patient received chemotherapy in the past to treat a different cancer.

Whether there is a history of a blood disorder such as myelodysplastic syndrome.

Whether the cancer has spread to the central nervous system.

Whether the cancer has been treated before or recurred (come back).

There is no standard staging system for adult AML

The disease is described as untreated, in remission, or recurrent.

A. Untreated adult AML

In untreated adult AML, the disease is newly diagnosed. It has not been treated except to relieve signs and symptoms such as fever, bleeding, or pain, and the following are true:

The complete blood count is abnormal.

At least 20% of the cells in the bone marrow are blasts (leukemia cells).

There are signs or symptoms of leukemia.

B. Adult AML in remission

In adult AML in remission, the disease has been treated and the following are true:

The complete blood count is normal.

Less than 5% of the cells in the bone marrow are blasts (leukemia cells).

There are no signs or symptoms of leukemia in the brain and spinal cord or elsewhere in the body.

C. Recurrent Adult AML

Recurrent AML is cancer that has recurred (come back) after it has been treated. The AML may come back in the blood or bone marrow.

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

Treatment for Acute Myeloid Leukemia

This is a disease which need to be treated by haematologist in specialized center.

If the patient had pancytopenia , supportive measures are used to correct them by packed red blood cells for

anemia , granulocyte colony stimulating factor for leucopenia , and platelet concentrate for

thrombocytopenia.

The patient should be admitted to haematology department and quick screening for external orifices should

be carried out to look for infections.

Because AML is a group of related diseases, treatment depends upon each subtype as well as on other factors.

It is important to start treatment as soon as possible after diagnosis.

The 2 treatment phases of adult AML are:

Remission induction therapy: This is the first phase of treatment. The goal is to kill the leukemic cells in the blood and bone marrow. This puts the leukemia into remission.

Post-remission therapy: This is the second phase of treatment. It begins after the leukemia is in remission. The goal of post-remission therapy is to kill any remaining leukemia cells that may not be active but could begin to regrow and cause a relapse. This phase is also called remission continuation therapy.

You may have more than one type of treatment, including:

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy).

When chemotherapy is placed directly into the cerebrospinal fluid(intrathecal chemotherapy), an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). Intrathecal chemotherapy may be used to treat adult AML that has spread, or may spread to the brain and spinal cord.

Combination chemotherapy is treatment using more than one anticancer drug. The way the chemotherapy is given depends on thesubtype of the cancer being treated and whether it has

spread to the brain and spinal cord.

AML treatment consists of two parts: induction therapy and consolidation therapy, which are both done in

the hospital.

The goal of induction therapy is to achieve remission by:

1. Killing as many AML cells as possible

2. Returning blood counts to normal over time

3. Ridding the body of signs of disease for a long time

Even if remission is achieved, you will likely still need more treatment. Consolidation therapy attacks leukemia

cells that common blood or marrow tests can't find. This therapy may include chemotherapy, which may be

different drugs than those used earlier, and possibly a bone marrow transplant.

Age, health, and other factors clearly need to be taken into account when considering treatment options. Doctors

are also trying to determine whether people with certain gene or chromosome changes are more likely to benefit

from more intensive treatment.

In younger patients, such as those under 60, induction often involves treatment with 2 chemo

drugs, cytarabine (ara-C) and an anthracycline drug such as daunorubicin (daunomycin) or idarubicin.

Sometimes a third drug, cladribine(Leustatin, 2-CdA), is given as well. The chemo is usually given in the hospital

and lasts about a week.

Patients with poor heart function can’t be treated with anthracyclines, and so may be treated with another chemo

drug, such as fludarabine (Fludara) or topotecan.

Induction destroys most of the normal bone marrow cells as well as the leukemia cells. Most patients develop

dangerously low blood counts, and the patient may be very ill.

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

Most patients need antibiotics and blood product transfusions. Drugs to raise white blood cell counts may also

be used. Blood counts tend to stay down for weeks. Usually, the patient stays in the hospital during this time.

About 1 or 2 weeks after chemo is done, the doctor will check a bone marrow biopsy. It should show few bone

marrow cells (hypocellular bone marrow) and only a few blasts (less than 10%). Over the next few weeks, normal

bone marrow cells will return and start making new blood cells. The doctor may check other bone marrow

biopsies during that time. When the blood cell counts recover, the doctor will check cells in a bone marrow

sample to see if the leukemia is in remission. If the biopsy done a week or 2 after the chemo treatment shows that

there are still leukemia cells in the bone marrow, more chemo may be given. Sometimes a stem cell transplant is

recommended at this point. If it isn’t clear looking at the first bone marrow whether the leukemia is still there,

another bone marrow biopsy may be done again in about a week.

Remission induction usually does not destroy all the leukemia cells, and a small number often persist. Without

consolidation treatment, the leukemia is likely to return within several months.

Chemotherapy, the use of anticancer drugs -- often two or three -- such as cytarabine, anthracycline drugs, 6-

thioguanine, hydroxyurea, or prednisone.

Consolidation (post-remission therapy):

Induction is considered successful if remission is achieved. Further treatment is then given to try to destroy any

remaining leukemia cells and help prevent a relapse. This is called consolidation.

For younger patients, the main options for AML consolidation therapy are:

I. Several cycles of high-dose cytarabine (ara-C) chemo (this is sometimes known as HiDAC)

II. Allogeneic (donor) stem cell transplant

III. Autologous stem cell transplant

Consolidation chemo differs from induction therapy in that usually only cytarabine is used. The drug is given at

very high doses, typically over 5 days. This is repeated about every 4 weeks, usually for a total of 3 or 4 cycles.

Another approach after successful induction therapy is a stem cell transplant. Patients first receive very high

doses of chemo to destroy all bone marrow cells. This is followed by either an allogeneic (from a donor) or

autologous (patient’s own) stem cell transplant to restore blood cell production. Stem cell transplants have been

found to reduce the risk of leukemia coming back more than standard chemo, but they are also more likely to

have serious complications, including an increased risk of death from treatment.

Older patients or those in poor health may not be able to tolerate such intensive consolidation treatment. Often,

giving them more intensive therapy raises the risk of serious side effects (including treatment-related death)

without providing much more of a benefit. These patients may be treated with:

1. 1 or 2 cycles of higher dose cytarabine (usually not quite as high as in younger patients)

2. 1 or 2 cycles of standard dose cytarabine, possibly along with idarubicin or daunorubicin

Non-myeloablative stem cell transplant (mini-transplant)

It is not always clear which of the treatment options is best for consolidation. Each has pros and cons. Doctors

look at several different factors when recommending what type of post-remission therapy a patient should

receive.

These include:

1. How many courses (cycles) of chemo it took to bring about a remission?

If it took more than one course, some doctors recommend that the patient receive a more intensive program, which

might involve a stem cell transplant.

2. The availability of a brother, sister, or an unrelated donor who matches the patient’s tissue type?

If a close enough tissue match is found, an allogeneic (donor) stem cell transplant may be an option, especially

for younger patients.

3. The potential of collecting leukemia-free bone marrow cells from the patient?

If lab tests show that a patient is in remission, collecting stem cells from the patient’s bone marrow or blood for

an autologous stem cell transplant may be an option. Stem cells collected from the patient would be purged

(treated in the lab to try to remove or kill any remaining leukemia cells) to lower the chances of relapse.

4. The presence of one or more adverse prognostic factors, such as certain gene or chromosome

changes, a very high initial white blood cell count, AML that develops from a previous blood disorder or

after treatment for an earlier cancer, or spread to the central nervous system?

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES

These factors might lead doctors to recommend more aggressive therapy, such as a stem cell

transplant. On the other hand, for people with good prognostic factors, such as favorable gene or

chromosome changes, many doctors might advise holding off on a stem cell transplant unless the

disease recurs.

5. The age of the patient. Older patients may not be able to tolerate some of the severe side effects that

can occur with high-dose chemo or stem cell transplants.

6. The patient’s wishes. There are many issues that revolve around quality of life that must be discussed.

An important issue is the higher chance of early death from high-dose chemo or a stem cell transplant.

This and other issues must be discussed between the patient and the doctor.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiationtherapy uses a machine outside the body to send radiation toward the cancer. Internal radiationtherapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.

Radiation therapy, the use of high-energy radiation to kill cancer cells. This is not used often for AML but may be

used to treat leukemia in the brain, bone, or testicles; before a stem cell transplant; or, in rare cases, to shrink a

tumor that's pressing on the windpipe.

A bone marrow transplant, which involves use of high doses ofchemotherapy and possibly radiation, followed

by a transplant of bone-forming stem cells. Stem cells usually come from a donor. Or, less likely, they come from

your own bone marrow or peripheral blood. If you cannot tolerate high doses of chemotherapy and radiation,

lower doses may be used with a "mini-transplant."

What are the survival rates for acute myeloid leukemia?

The five-year survival rate overall is about 24%. Surviving at least five years indicates a good chance of long-term

survival. Survival rates may be better now as this statistic reflects outcomes from 1999 to 2006.

.

Treating frail, older adults

Treatment of AML in people under 60 is fairly standard. It involves cycles of intensive chemo (discussed above). Many

patients older than 60 are healthy enough to be treated in the same way, although sometimes the chemo may be less

intense. People who are much older or are in poor health may not be able to tolerate this intense treatment. In fact, intense

chemo could actually shorten their lives.

In some cases, doctors may recommend low-intensity chemo with a low dose of cytarabine given in cycles. In some cases,

this may induce remission. In others, it may control the leukemia for a time. Treatment of these patients is often not

divided into induction and consolidation, but may be given every so often as long as it seems helpful.

Sometimes, these patients may be treated with drugs used to treat myelodysplastic syndrome, like 5-azacytidine(Vidaza)

or decitabine (Dacogen). These drugs are not approved to treat AML, but still may be helpful.

Some patients decide against chemo and other drugs and instead choose supportive care. This focuses on treating any

symptoms or complications that arise and keeping the person as comfortable as possible.

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ACUTE MYELOBLASTIC LEUKEMIA DR MAGDI AWAD SASI 2014 DETAILED APPROACH WITH SLIDES