Engidaw Ambelu

1. leukemia
By Dr. Damena M.(MD)

2. Presentation out line
• introduction
• Acute myelogenous leukemia
• Acute lymphoblastic leukemia
• Chronic myelogenous leukemia
• Chronic lymphoblastic leukemia

3. Introduction
Definition
• Leukemia are a group of malignant disorder of
hematopoietic tissue characterized by increased no. of
blast cells in bone marrow.
• This cells are proliferate in uncontrolled fashion and
replace normal bone marrow elements.

4. • Classification
• Acute:have brief symptomatic period with short life expectancy
without treatment
• Myelogenous
• lymphoblastic
• Chronic:- the patient are un well for years and survival is long (
usually in years)
• Myelogenous
• Lymphoblast
• Sub leukemic leukemia:- normal or sub-normal leucocyte count but
blasts ( immature blood cells)are seen on peripheral
morphology
• Aleukemic leukemia:- normal or sub normal leucocyte count and
also no blast seen on peripheral morphology. diagnosis is by
taking bone marrow biopsy and seeing blast cells.

5. RBC
Bone Marrow Hematopoiesis
Pluripotent
Stem Cell
Myeloid
Stem Cell
Lymphoid
Stem Cell
Platelet PMN Eos Baso Mono
T-
lympho
blast
B-
lympho
blast
B-cell
Erythro-
blast
Myeloblast
Meg-
blast
T-cell
Plasma
cell
Monoblast

6. Acute myelogenous leukemia
• AML is characterized by a clonal proliferation of myeloid
precursors with a reduced capacity to differentiate into more
mature cellular elements.
• As a result, there is an accumulation of leukemic blasts or
immature forms in the bone marrow, peripheral blood, and
occasionally in other tissues, with a variable reduction in the
production of normal red blood cells, platelets, and mature
granulocytes.

8. INCIDENCE
• In 2013, the estimated number of new AML cases in the
United States was 14,590.
• The incidence of AML is ~3.5 per 100,000 people per
year
• the age-adjusted incidence is higher in men than in
women (4.5 vs 3.1)
• AML incidence increases with age; it is 1.7 in individuals
age <65 years and 15.9 in those age >65 years.
• The median age at diagnosis is 67 years.

9. ETHIOLOGY
• Exact etiology of AML is unknown.
• Heredity
• Genetic fragility
• Bloom syndrome= autosomal disorder
• Fanconi anemia =reduce produced cells
• Wiskott Aldrich =thrombocytopnia
• Down, Klinefelter, Patau syndromes
• Myeloproliferative syndromes
• Radiation exposure; High dose like in atomic bomb survival of japan.
Therapeutic radiation have no or little effect
• Chemical and other exposures
• Benzene, cigarette smoking, petroleum products
• herbicides?, pesticides?
• Drugs
• Topoisomerase II inhibitors (e.g etopisode), alkylating agents
• Chloramphenicol, chloroquine

10. Classification
• WHO classification- based on
• Morphology
• Clinical features, and
• Cytogenetic and molecular abnormalities
• Uses 20% blast cut-off for a diagnosis of AML
• Useful for targeted therapy
• FAB (French-American-British )classification
• Based on morphology and cytochemistry
• AML is defined as the presence of >30% blasts in the BM
• 5-30% blast is considered as MDS=myelodysplastic syndrome
• Still utilized by pathologists due to its simplicity

11. FAB Classification of AML
• M0- undifferentiated acute myeloblastic leukemia
• M1 -AML with minimal maturation
• M2- AML with maturation
• M3 -Acute promyelocytic leukemia
• M4- Acute myelomonocytic leukemia
• M4Eo - Acute myelomonocytic leukemia with eosinophilia
• M5- Acute monocytic leukemia
• M6 -Acute erythroid leukemia
• M7 -Acute megakaryoblastic leukemia

12. Clinical feature
• Symptoms are the consequence of anemia, leukocytosis,
leukopenia, or thrombocytopenia
• Fatigue- the most common symptom
• Anorexia and weight loss
• Fever with or without an identifiable infection
• Bleeding and easy bruising
• Occasionally, bone pain, LAP, nonspecific cough,
headache, or diaphoresis

13. • Myeloid sarcoma- a tumor mass consisting of myeloid
blasts occurring at anatomic sites other than bone
marrow
• Common sites include the skin, lymph node, GIT, soft tissue,
and testis
• Physical findings
• Fever, hepatomegaly, splenomegaly, and LAP
• Sternal tenderness
• Bleeding from GIT, pulmonary, or intracranial
• Retinal hemorrhages
• Infiltrations of the gingivae, skin, soft tissues, or meninges
with leukemic blasts

16. Lab evluation
• CBC
• 25-40% of pts have WBC count <5000/µl, and 20% have counts >100,000/µl
• Anemia is usually present and can be severe
• Platelet count <100,000/µl- 75% of pts
• Serum uric acid and LDH
• LFT and RFT
• Serum electrolytes
• Bone marrow aspirate and biopsy- for morphology, cytogenetics, flow
cytometry, molecular studies
• Lumbar puncture for those with symptoms of CNS involement

17. • Viral serologies for HIV, CMV, HSV-1, varicella-zoster
• HLA typing for potential allogenic HSCT
• PA and lateral chest X-ray
• echocardiography
• Diagnostic criteria
• Previously >30% blasts on BM aspirate (per FAB criteria)
• Recently changed to > 20% blasts on BM aspirate (per WHO
criteria)

19. Treatment of AML
Goal for complete remission
• platelet count greater than 100,000
• neutrophil count greater than 1000
• BM with 5% or less blasts with no Auer rods
• No circulating blasts
• No extramedullary leukemia
• Molecular complete remission : no evidence of leukemic
cells in BM even with sensitive tests (eg, PCR, flow
cytometry)
• If in complete remission for >3 yrs without relapse →
potentially cured (<10% chance of relapse)

20. Remission induction therapy
• Commonly anthracycline (ie, daunorubicin, idarubicin) and cytarabine →
(“3+7 regimen”)
• Cytarabine has ample CNS penetration so no need for prophylactic intrathecal
chemotx (also, ↓ risk in patients with AML compared to ALL)
• 60-80% achieve complete remission
Post remission therapy
1. Consolidation
– longer survival than maintence alone
– typically high dose cytarabine
2. Maintenance – continue chemotx monthly for 4-12 months
– nonmyelosuppressive doses

21. Increasingly, hematopoietic cell transplantation is used in patients with
AML after 1st remission in those with poor/intermediate
prognostic factors.
• Also allogenic/autologous transplant in those with relapse or
2nd remission
• autologous with higher relapse rates
• Used in those without HLA matched donor
• Standard therapy → remission rates of 60-80% with median remission
durations of 1 yr
• less than 20% achieve long-term remission free survival
• Therapy is altered in older individuals (esp. those with poor
performance status)
• AML believed to be a clinically/biologically distinct entity in older individuals →
remission rates of 45% in those > 60 yo with less than 10% long-term remission
free survival
• low dose cytarabine +/- hydroxyurea
investigational therapy
palliative care

22. • Supportive care
• G-CSF
• platelet transfusions
• PRBCs (leukodepleted, irradiated)
• Prophylactic antibiotics
• Cefepime/ceftazidime
• fluconazole (candidiasis)
• acyclovir (HSV, VZV)
• Prevention of hyperuricemia with hydration and allopurinol
and/or rasburicase

24. Prognostic Factors in AML
• Favorable
• younger age (<50)
• WBC <30,000
• Favorable cytogenetics and molecular findings
• Achievement of CR with single course of chemotherapy
• Unfavorable
• older age (>60)
• Poor performance status
• WBC >100,000
• Elevated LDH
• prior MDS or myeloproliferative disorders
• AML developing after treatment with cytotoxic agents
• Comorbidities
• A prolonged symptomatic interval with cytopenias preceding diagnosis

25. ACUTE LYMPHOBLASTIC LEUKEMIA
(ALL)
• Commonest form of malignancy in childhood
• Peak incidence at 4 – 5 yrs of age
• Acute onset with short history of duration
• 85% are B cell , 15% are T cell

26. PREDISPOSING FACTORS
• HEREDITARY
• AQUIRED
• Ionizing radiations
• Therapeutic radiations
• Nuclear fallout
• Diagnostic X-rays
• Chemical agents

27. Clinical presentation• FEVER
• FATIGUE
• BONE /JOINTS PAIN
• WEIGHT LOSS
• PURPURA AND BLEEDING MANIFESTATION
• LYMPHADENOPATHY-
• HEPATOSPLENOMEGALY
• STERNAL TENDERNESS
• MEDIASTENAL MASS

28. FAB CLASSIFICATION
 ALL L1
 ALL L2
 ALL L3
 In childhood – L1 is the most common type
 In adults – L2 is the most common type

29. FAB classification
Morphology L1 L2 L3
1 Size of blast Small Large heterogeneous Large
homogenous
2 Cytoplasm Scanty Moderate Moderate,
intensely
basophilic
3 N/C Ratio High Lower Lower
4 Cytoplasmic vacuoles +/- +/- Prominent
5 Nuclear membrane Regular Irregular with clef
ting
Regular
6 Nucleoli Invisible /
indistinct
Prominent 1-2 Prominent 1-2

30. DIAGNOSIS OF ACUTE LEUKEMIA
• Peripheral Blood smear
• Bone marrow aspiration smear
• Cytochemistry
• Immunophenotyping
• Cytogenetic analysis
• Molecular genetic analysis

31. PERIPHERAL BLOOD EXAMINATION
 Total leukocyte count raised , normal or low
 Normocytic normochromic anaemia
 Thrombocytopenia

32. BONE MARROW EXAMINATION
• Hypercellular
• Normal hematopoietic elements diminished
• Increased blasts

33. PROGNOSTIC FACTORS
Factor Good prognosis Bad prognosis
Race White Black
Age 2-8 yrs <1yr.,adult, >10 yrs
Sex Female Male
Meningeal involvement - +
Lymphadenopathy, liver,
spleen
- Massively enlarged
Mediastinal mass - +
TLC <20x109 /L >50 x109 /L
Type of ALL L1 L2,L3
Cytogenetics Hyperdiploidy >50 chromosomes Pseudodiploidy, t (4;11),t (9;22), BCR-ABL fusion
m RNA, MLL-AF4 fusion mRNA.
Immuno-phenotype B-ALL,CD 10+, Early pre-B cell T-ALL in children

34. Treatment
• Induction phase
• High dose chemotherapy
• Consolidation phase
• High dose systemic therapy
• CNS prophylaxis
• Maintenance phase
• Prevent relapse
• Effect cure
• Supportive care
• The overall cure rate in children is 90%, while 50% of adults are long-term disease-free survivors

35. ALL Vs AML
ALL AML
Age Mainly children Mainly adults
Lymphadenopathy Usually present Usually absent
Hepatosplenomegaly +ve mild +ve mild
Gum hypertrophy -ve +ve in M4/M5
Skin infiltration -ve +ve in M4/M5
CNS involvement +ve in some +ve in some
Granulocytic sarcoma -ve +ve in few cases
Mediastinal mass +ve in T-ALL -
Associated DIC -ve +ve in M3
Serum muramidase Normal In M4/M5 (monocytic type)
Prognosis Good Bad

36. Chronic Myeloid Leukemia
(CML)
• is a clonal expansion of a hematopoietic stem cell possessing a reciprocal
translocation between chromosomes 9 and 22 called Philadelphia chromosome
• Occurs more often in men
• Incidence increases with age
• High doses of ionising radiation can increase the occurrence of CML
• No clear correlation with exposure to cytotoxic drugs has been found, and no
evidence suggests a viral etiology

37. Pathophysiology
• Genetic hallmark of CML is the presence of BCR-ABLfusion gene product
• The fusion protein is a result of reciprocal translocation between the
abelson oncogene on chromosome 9 and break point cluster region on
chromosome 22.
• Attachment of the BCR sequences to ABL1 results in three critical
functional changes
I. The ABL protein becomes constitutively active as a tyrosine kinase enzyme,
activating down stream kinases that prevent apoptosis
II. The DNA-protein-binding activity of Abl is attenuated; and
III. The binding of Abl to cytoskeletal actin microfilaments is enhanced

39. Clinical presentation
Symptoms
• Fatigue,malaise
• Weight loss
• Early satiety
• Left upper quadrant pain or mass
• Easy bruising ,bleeding
• Fever
Uncommon presentation
• Acute gouty arthritis,priapism,myocardial infarction,venous thrombosis,visual disturbance

40. Signs
• pallor
• Splenomegaly
• Sternal tenderness
• Lymhadenopathy
• Hepatomegaly
• Purpura
• Retinal haemorrhage

41. Diagnostic approach
Peripheral blood
• Granulocytic leukocytosis>50*10p9/l
• Predominance of neutrophils and increased % of myelocytes
• Absolute basophilia
• Platelets are normal or increased in number
Bone marrow
• Marrow is hypercellular with granulocytic predominance
• Megakaryocytes are increased in number with abnormal morphology
• Increase in reticulin fibrosis
• Blasts less than 5%

42. Phases of CML
chronic phase
• Elevated WBCs
• <5% circulating blasts
• Majority of the cells are myelocytes, metamyelocytes, and
band forms
Accelerated phase
• Blasts 10-20% in peripheral blood and/or bone marrow
• Basophils >20% in peripheral blood
• Increasing degrees of anemia unaccounted for by bleeding or
therapy
• Persistent thrombocytopenia
• Cytogenetic evidence of clonal evolution

43. Blast crisis phase
• Blast > 20%- acute leukemia
• Extramedullary blast proliferation
• Large aggregates or clusters of blast in bone marrow
• Hyposegmented neutrophils may appear
• Occurrence of de novo blast crisis or following imatinib
therapy is rare

44. Treatment
• Drugs
• Stem cell transplant
• Leukaphresis and splenectomy
drugs
• Imatinib mesylate,dasatinib,nilotinib
• Hydroxyurea
• busulphan
• Interferon-alpha
• Homoharringtonine
• Anagrelide
• Cytarabin

45. Imatinib
• It is an ABL specific tyrosine kinase inhibitor
• Imatinib induces apoptosis in cells expressing BCR/ABL
• Dose is 400mg/day
• It should achieve cytogenetic remission by 6months and molecular remission by
18 months
• Side effects-edema,pleural and pericardial
effusion,nausea,vomiting,diarrhoea,muscle cramps,skin rash,bone pain and
arthralgia.myelosuppression.

46. Hydroxy urea
• Inhibitor of ribonucleotide reductase
• Lower the blood counts in 1-2 days
• Dose is 500-3000 mg/day
• Side effect-nausea and skin rash
• Given for patients intolerant to imatinib
Busulphan
• Gradually lowers the blood counts
• Dose-6-10 mg/day
• Should not be used in patients expected to undergo bone marrow
transplantation

47. Allogenic HSCT
• Outcome depends on patients age, phase of disease, type of
donor, preparative regimen, graft Vs host disease, post
transplantation treatment
• Patients age should be less than 70 years. transplantation from
donor should be HLA matched
• Peripheral blood can be used a source of haemotopoietic
progenitor cells. preoperative regimen like cyclophosphamide
plus total body irradiation is used
• Complications-graft Vs host disease

48. Chronic lymphocytic leukemia
(CLL)
• Chronic Lymphocytic Leukemia (CLL) is a low-grade Non-Hodgkin lymphoma
• It is main characteristic is
• proliferation of malignant clone of mature- appearing cells in the bone marrow with
leukemic component
• absolute lymphocytosis in the peripheral blood.
• In 90% of cases it originates from B-cell

49. Epidemiology
• B-cell chronic lymphocytic leukemia(CLL) -the most common lymphoproliferative
disorder in Western countries
• incidence
• 5/100,000-for males and
• 2.5/100,000 for females
• More common in whites than blacks
• Disease of older adults – median age-65-68 years
• CLL is exceedingly rare in children

50. Clinical features
• has a chronic course
• could be asymptomatic
• often is diagnosed accidentally on a routine blood count
• In symptomatic patients
• Splenomegaly
• LAP-the lymph nodes are nontender, non matted or fixed to surrounding
tissue
• Rarely- malaise, easy fatigability, weight loss, night sweats
• these symptoms usually correlate with the overall tumor load

51. CLINICAL FEATURES
• Anemia, thrombocytopenia, neutropenia due to-
• disease progression within the bone marrow;
• autoimmune complication;
• Hypersplenism; or
• treatment side effects
• Symptoms of immune defficiency-
• hypogammaglobulinemia – pulmonary bacterial infections;
• T-cell deficiency-more often result of treatment- high risk of viral and opportinistic infections
• Autoimmune manifestations such as
• autoimmune thrombocytopenia,
• Coombs positive hemolytic anemia, or
• pure red cell aplasia

52. LABORATORY STUDIES
• Increase in the number of mature-appearing lymphocytes in circulation to more than
5000/microL
• In the advance stages – anemia, thrombocytopenia
• In patients with very large tumor burden-elevated serum lactic dehydrogenase (LDH), beta2 –
microglobulin and uric acid levels
• In 5%- serum protein electrophoresis detects M-components(paraprotein)
• Often- hyppogammaglobulinemia
• Often- Coombs test is positive

53. LABORATORY STUDIES
• Peripheral smear shows increased numbers of small, mature appearing
lymphocytes
• Smudge cells
• Bone marrow generally shows a diffuse infiltration of small, mature-appearing
lymphocytes

54. DIAGNOSIS
- Absolute lymphocytosis- > 5000/ microL mature-appearing lymphocytes in
circulation
- Diffuse infiltration of bone marrow of small , mature –appearing lymphocytes
- Typical immunophenotyping of B-cells-CD19+; CD5+; CD23+; CD20+; low
amounts of sIg

56. TREATMENT AND PROGNOSIS
Prognostic factors:
• advanced stage
• lymphocyte doubling time < 6 months
• cytogenetic abnormalities , esp. del 17
• expression of CD38 and ZAP-70
• elevated LDH and beta 2 -microglobulin

57. Treatment and Prognosis
• The treatment of CLL with chemotherapy with or without transplantation is never
curative
• When patients are asymptotic, without large tumor burden and unfavorable
prognostic factors it is better option to delay treatment till progression of the
disease happens
.
• Chlorambucil
• oral alkylating agent
• response is obtained in 60-70% but is usually partial and last less 20 months

58. Treatment and Prognosis
• Fludarabine
• purine analog
• The overall response rate is 75% with a mean duration 25 months
• could be administated alone( complete response-20%) or in combination with
Cyclophosphamide ( complete response- 40%)
• Alemtuzumab-
• recombinant CD 52 –antibody which is shared by CLL-B cells and normal T cells
• Side effects- “ first dose effect”- rigors, fever, hypotension and respiratory distress; severe
immunosupression, reactivation of CMV

59. Complications
1. Autoimmune disease:
• Hemolytic anemia and thrombocytopenia. The treatment include
corticosteroids.
• Pure red cell aplasia- usually responds to cyclosporin
2. Severe infections:
• antibiotics,
• antiviral agents,
• sometimes administration of i.v. gamma globulin
3. Richter syndrome:
• transformation to diffuse large cell lymphoma or prolymphocytic
leukemia
• it is suspected when the disease’s course changes abruptly

60. Thank you very much
QUESTIONS???