Acute leukemia 2nd year students

ACUTE LEUKEMIA

Justiniano Castro MD

BLAST CELL: DEFINITON

Blast cells are immature cells found in the bone marrow. They are not fully developed, and therefore, do not carry out any normal function in the blood. More than 5% of these cells in the bone marrow is abnormal and need to be evaluated for the possibility of a malignant disorder of the hematopoietic system.

LEUKEMIA: DEFINITION

Leukemia is a malignant clonal condition of the bone marrow and blood. It is characterized by the acumulation of blast cells in the marrow, usually more than 20%. These blast cells are frequently seen in the peripheral blood.

LYMPHOID VS. MYELOID CELLS Immature lymphoid cells have minimal

differentiation Myeloid blast has some differentiation Cytoplasmic granules in myeloid cells

(auer rod) Cytochemical stains (mpo and pas) Immunological markers, Ig and TCR

Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.

Maslak, P. ASH Image Bank 2004;2004:101101

Figure 1. Arrow marks an Auer rod in this myeloid blast



Figure 1. Blasts may appear "rounded" or "regular" with scant cytoplasm

PATHOPHYSIOLOGY OF AL Leukemias typically fill up the marrow with abnormal

cells, displacing normal hematopoiesis. The marrow here is essentially 100% cellular, but composed almost exclusively of leukemic cells. Normal hematopoiesis is reduced via replacement (a "myelophthisic" process) or by suppressed stem cell division. Thus, leukemic patients are prone to anemia, thrombocytopenia, and granulocytopenia and all of the complications that ensue, particularly complications of bleeding and infection.

Bone marrow failure secondary to leukemic infiltration producing anemia, neutropenia and thrombocytopenia

Maturation arrest and lineage infidelity Chromosomal abnormalities involving oncogenes and

tumor suppressor genes

TECHNIQUE FOR ACUTE LEUKEMIA DIAGNOSIS

Morphologic features Cytochemical stains Flow cytometry and markers Chromosomal analysis Fluorescence In Situ hybridization

(FISH) PCR (polymerase chain reaction)

ACUTE LYMPHOBLASTIC LEUKEMIA This a clonal disorder of hematopietic

cells There is accumulation of immature cells

and tissue infiltration. Risk factors (chemicals, family history,

radiation and chemotherapy)


Maslak, P. ASH Image Bank 2007;2007:6-00053

Figure 2. A high power view reveals coarse chromatin with an irregular nuclear contour



Figure 11. Blasts have scant cytoplasm

ACUTE LYMPHOBLASTIC LEUKEMIA Accumulation of lymphoblast Most common in children and better

prognosis than adults (3-7years) Disease in children is different than

the adults Rise incidence after 40 years with a

very poor prognosis

CLASSIFICATION: ALL B VS. T

• Precursor B cell lymphoblastic leukemia/lymphoma, also called precursor B cell acute lymphoblastic leukemia (precursor B cell ALL)

• Precursor T cell lymphoblastic leukemia/lymphoma (precursor T-LBL), also called precursor T cell acute lymphoblastic leukemia (precursor T cell ALL)

CLASSIFICATION OF ALLFAB (L1, L2 and L3) Immunological (B vs. T lineage)B cell 80% of all ALL. Tcell 20% of

all ALL.B cell precursor ALL (80% ALL)

CD10,CD19,CD20 and CD22) markers Early pre-B, CD10 neg (infant). Usually

CD34+ Pre-B, CD10+ (common ALL) B-ALL (Burkitt’s type or L3, large vacuole

and surface immunoglobulin). Its now consider a lymphoma

T-cell ALL (TdT, CD3, CD5 and CD7)

DIAGNOSIS OF ALL

Peripheral smear with blast cellsBone marrow with >20% of blasts Immunophenotype

B vs. T cell, markersHelp to differentiate from myeloid

Chromosomal analysis (Hyper vs.hypodiploidy, t(9;22) or Ph+, t(4;11), t(v;11q23),t(12;21) and t(1;19))

SPECIAL TEST IN ALL Due to high incidence of CNS

involvement a lumbar puncture is usually required and intrathecal treatment

CT’s Scan for T cell and Burkitt Testicular us Tumor lysis syndrome

CYTOGENETICS IN ALL Philadelphia Chromosome present in 30% of

adult ALL with a very poor prognosis. T(4;11) association with secondary leukemia T(v;11q23),t(12;21) and t(1;19) TEL and AML1 genes are present in 30% of

childhood ALL and is associated with a good proognosis.

Tyrosine Kinase inhibitors are included in treatment strategies

TREATMENT OF ALLCytotoxic chemotherapy include

induction, consolidation, intensification and maintenance

Complete response after induction is 80%

Cure 35-40% in the adult population

T cell and L3 ALL require special consideration

Response and cure in children could be as high as 90%

PROGNOSIS IN ALLCure rate of 75-90% in children’sCure rate in adults of 30% CD10 negative ALL has worse

prognosisA presentation with a WBC >

30,000/m3 is associated with a poor prognosis

CytogeneticsSlow response to induction is

considered a poor prognosis feature

SUPPORTIVE CARE IN AL

Blood products Hydration and treatment with allopurinol

Prevention of N/VAggressive antibiotic cover

Central line catheters

SALVAGE THERAPY IN ALBone marrow transplantCord Blood TransplantExperimental treatment

ACUTE MYELOGENOUS LEUKEMIA

CLINICAL OVERVIEW Acute myeloid leukemia (AML) is the most common acute

leukemia in the adult AML is cancer of the blood-forming tissue (bone marrow). Normal bone marrow produces red cells, white cells, and

platelets. AML causes bone marrow to produce too many immature

white blood cells (blast cells) . Suppresses normal blood cell production.

Anemia, leucopenia, thrombocytopenia

RISK FACTORS

Age Older adults are more likely to develop AML

Smoking 20% of AML cases are linked to smoking Doubles the risk of disease in people > 60 y/o

Genetic disorders Down syndrome, Fanconi’s anemia

High doses of radiation Long-term survivors of atomic bombs

Previous chemotherapy treatment Breast cancer, ovarian cancer, lymphoma

Exposure to industrial chemicals Benzene long term exposure

3-5 new cases expected per 100,000 population

8,900 estimated deaths/year M:54%, F:46%

STATISTICS

5-year survival rate in adults under 65 is 33%

5-year survival rate in adults over 65 is 4-5%

Incidence:

Mortality:

Prognosis:

Prognosis:

Prognosis:

Incidence:

Mortality:

Prognosis:

Prognosis:

Prognosis: 20-30% experience remission or are cured

Sources: American Cancer Society; The Leukemia & Lymphoma Society,

CLINICAL FEATURES OF AML

Bone marrow failureCoagulopathy (DIC) specially in APL

Tumor infiltration of monocytic leukemia

Tumor lysis syndrome specially with the initial chemotherapy

CLASSIFICATION BY FAB Mo

Undifferentiated(5%) M1 no

maturation(20%) M2 maturation(30%)

M3 Promyelocytic (7%)

M4 myelomonocytic

M5 monocytic

M6 Erythroleukemia (very rare)

M7 Megakarioblast (very rare)

AML BLAST WITH AUER ROD

THE WHO CLASSIFICATION

Reduce the percentage of blast to 20%

Emphasis in the Cytogenetic characteristics

Recognize therapy related leukemia's

Recognize AML from previous Myelodyplasia

CYTOGENETIC IN AML

Good prognostic groupT(15;17)T(8;21)Inv (16)

(p13q22) with eosinophilia

Poor prognostic groupDeletion of chromosome 5/7t(11;q23)t(6;9)

+8Complex rearrangement

CYTOCHEMICAL STUDIES AND MARKERS

MPO or Sudan blackNonspecific esterasePeriodic Acid Shift (PAS)Markers CD13, CD33 an CD15 are only helpful for diagnosis of AML

AML – PEROXIDASE STAIN

Blast with + MPD

Acute Myelogenous Leukemia M2

T(8;21) (q22;q22) RUNX1-RUNX1T1 (TEL and AML1 genes)

Constitute 7% of AMLAuer rods are easily identified and

cytoplasm is generally basophilicFavorable prognosis in adults but

not in children

Myeloid maturational arrest is demonstrated in this image, AML M2

ACUTE MYELOGENOUS LEUKEMIA M4Approximately 20% of AML but 5%

of them are AML M4 with eosinophilia and inv(16)

Mixture of blast with myeloid and monocytic features

Better prognosis with the inv(16) expression.

The dysphasic eosinophil precursors , AML M4 inv(16) eos

ACUTE PROMYELOCYTIC LEUKEMIA

DIC very frequent t(15;17) is present in almost every case RAR gene present in chromosome 17

juxtaposition with PML gene in chrom 15 producing a maturation arrest

All transretinoic acid (ATRA) induce maturation

AML M3 FAGGOT

Cells with multiple Auer rods (arrow) may be appreciated AML M3

ACUTE PROMYELOCYTIC LEUKEMIA

Retinoid acid syndrome is associated with an increase in WBC counts with respiratory problems, fever and hypotension

Arsenic trioxide is active in this leukemia

Antracyclines are essential in the treatment

Proliferation: FLT3, Normal Cytogenetics A receptor tyrosine

kinase expressed in 70 – 100% of AML cases.

Activating mutations in FLT3 are seen in ~30% of AML cases. Tandem duplication

of the juxtamembrane region.

Point mutation within the activation loop of the kinase domain.

Activation of FLT3 leads to deregulated proliferation of AML cells.

MANAGEMENT OF AML Supportive treatment similar to all AL AML M3 need special attention to DIC Monocytic leukemia's can infiltrate CNS,

gingival and skin Induction chemotherapy produce 70%

CR Usually 3 consolidation treatments Cure between 35 to 40% of the patients MUGA scan is necessary as one of the

initial test for evaluation of cardiovascular function

SALVAGE TREATMENT IN AML

Allogeneic BMT can cure high risk and relapse AML

Monoclonal antibodiesExperimental therapy

MYELODYSPLASTIC SYNDROME

A heterogeneous group of hematopoietic disorders characterized by peripheral blood cytopenias and hypercellular marrow

Clonal malignant disorder of the hematopoietic cells

Transformation to AML is frequent

FAB CLASSIFICATION IN MDS

Refractory anemia

RA with ring sideroblast

RA excess of blast

Chronic myelomonocytic leukemia

RA with excess of blast in transformation (RAEBT)

MDS WITH DYSERYTHROPOIESIS


Vardiman, J. W ASH Image Bank 2001;2001:100189

Figure 7. Refractory anemia with ringed sideroblasts (RARS)

WHO CLASSIFICATION OF MDS

RA RARS Refractory anemia with multilineage

dysplasia (RCMD) RAEB 5q- syndrome Unclassifiable


Vardiman, J. W ASH Image Bank 2001;2001:100188

Figure 9. Refractory cytopenia with multilineage dysplasia (RCMD)

PROGNOSIS OF MDS

Presence of blast indicate poor prognosis Uniformly fatal disorder due to infection and

bleeding Chromosomal abnormalities are frequent

including partial loss of chromosome 5, 7 and trisomy 8

5q- syndrome usually involve band q13 to q33 with anemia but no thrombocytopenia

The International Prognostic Index ( % blasts cells, cytogenetic and number of cytopenias)

PATHOGENESIS OF MDS

Toxic exposure and genetic predisposition Immune response Hypermethylation and angiogenesis RAS mutation as a late effect Transformation

TREATMENT OF MDS BY RISK STRATIFICATION Cytogenetics Blast % No. cytopenias

Antiangiogenic Factor( Lenalidomide and thalidomide)

Hypomethylating agents Azacytidine and dezacitidine)

Bone Marrow Transplantation

Education

Acute leukemia 2nd year students