1. Leukemias The development of Leukemia Acute Lymphocytic Leukemia (ALL)
uncontrolled and accelerated production of haematopoietic stem cell, progenitors, or mature blood cells which results in incomplete or defective cell maturation
Acute Lymphocytic Leukemia (ALL)
Acute Mylogenous Leukemia (AML)
Chronic Lymphocytic Leukemia (CLL)
Chronic Mylogenous Leukemia (CML)
Copyright, 1996 © Dale Carnegie & Associates, Inc.

2. Demographics of Leukemia Patients
CLL=Chronic Lymphocytic
ALL=Acute Lymphocytic
CML=Chronic Mylogenous
AML=Acute Mylogenous

3. Stem cells and growth factors in haematopoietic cell development.
page 1003

4. Hematopoietic stem cells give rise to two major progenitor cell lineages, myeloid and lymphoid progenitors

5. Myeloproliferative disorders
ALL MM
CLL
Lymphomas
naïve
germinal center
B-lymphocytes
Plasma
cells
Lymphoid
progenitor
T-lymphocytes
Hematopoietic
stem cell
AML
Myeloproliferative disorders
Neutrophils
Eosinophils
Basophils
Monocytes
Platelets
Red cells
Myeloid
progenitor

8. Acute leukemia is characterized by a rapid increase
in the numbers of immature blood cells. Crowding due to such cells makes the bone marrow unable to produce healthy blood cells. Immediate treatment is required in acute leukemia due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. Acute forms of leukemia are the most common forms of leukemia in children.

9. Chronic leukemia
is characterized by the excessive build up of relatively mature, but still abnormal, white blood cells. Typically taking months or years to progress, the cells are produced at a much higher rate than normal cells, resulting in many abnormal white blood cells in the blood. Whereas acute leukemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy. Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group.

10. Main Signs and symptoms
1. Hyperplasia or hyperproliferation of affected cell - uncontrolled proliferation of malignant cells and their spreading (in bone marrow, peripheral blood and organ infiltration (spleen (nausea or feeling of fullness due to an enlarged liver and spleen), lymph nodes, skin, gastrointestinal tract, central nervous system (neurological symptoms (headaches)).

11. Main Signs and symptom
2. Malignant cells replace normal bone marrow elements leading to
a) anemia (clinical manifestation - dyspnea and pallor),
b) thrombocytopenia (people with leukemia may easily become bruised, bleed excessively, or develop pinprick bleeds (petechiae),
c) neutropenia (clinical manifestation - frequent infection, ranging from infected tonsils, sores in the mouth, or diarrhea to life-threatening pneumonia or opportunistic infections),

12. Main Signs and symptom
3. Nonspecific symptoms of intoxication (feeling sick, such as having fevers, chills, night sweats and other flu-like symptoms, or feeling fatigued),
4. Metabolic and Electrolyte Abnormalities

13. Pictures Of Blood Normal human blood Blood with leukemia Blasts
Red Cell
Platelet
White Cell
Normal human blood
White Cell
Red Cell
Platelet

14. Development of Leukemia in the Bloodstream
Stage 1- Normal
Stage 2- Symptoms
Stage 3- Diagnosis
Stage 5a- Anemia
Stage 5b- Infection
Stage 4- Worsening
Legend
White Cell
Red Cell
Platelet
Blast
Germ
Sources from Leukemia, by D. Newton and D. Siegel

15. DEFINITION
Acute leukemias are clonal malignant hematopoietic disorders resulting from genetic alterations in normal hematopoietic stem cells. These alterations disrupt normal differentiation and/or cause excessive proliferation of abnormal immature “leukemic” cells or “blasts.” As the disease progresses, leukemic cells accumulate in the bone marrow, blood, and organs, displacing normal progenitor cells and suppressing normal hematopoiesis.

16. Clinical presentation
Common symptoms of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are a reflection of bone marrow failure and include fatigue, bruising or bleeding, fever, and infection.
Pancytopenia:
WBCinfection.
Hb anemia.
platelets bleeding.
Organ infiltration:
Lymphadenopathy.
Splenomegally.
Hepatomegally.
CNS: 5-10% of patient with ALL

17. Investigations: CBC: 60% of pts have an elevated WBC. Most are anemic
Most are thrombocytopenic
90% have blast in the periphral blood film.
electrolytes:
Hypo/hyper kalemia
Hypomagnesimia
hyperphosphatemia
Hypermetabolism:
LDH.
uric acid.
DIC:
Most common with promyelocytic leukemia, small% monocytic leukemia & ALL
Bone marrow biopsy and aspirate:
30%or more of all nucleated cells are blast.
Radiology:
CXR: mediastinal mass(T-cell ALL)
Osteopenia or lytic lesion 50% of patients with ALL.(itractable pain).

18. Acute leukemia diagnostic algorithm.

19. Lymphoblast/myeloblast

21. Acute lymphoblastic leukemia ALL-L1

22. Acute lymphoblastic leukemia ALL-L1

23. Acute lymphocytic leukemia ALL-L2

24. Acute lymphocytic leukemia ALL-L3

25. Acute lymphocytic leukemia ALL-L3

26. Acute myeloid leukemia AML-M0

27. Acute myeloid leukemia AML-M1

28. Acute myeloid leukemia AML-M2

29. Acute myeloid leukemia AML-M2 + peroxidase

30. Acute myeloid leukemia AML-M3

31. Acute myeloid leukemia AML-M3 hypogranular

32. Acute myeloid leukemia AML-M4

33. Acute myeloid leukemia AML-M5

34. Acute myeloid leukemia AML-M6

35. Acute myeloid leukemia AML-M7

36. Management: A-Supportive measure:
-isolation in positive laminer flux room
-insertion of central line
-family and patient support by permanent social worker
-AlKaline diuresis to prevent tumor lysis syndrome
-oropharynx/GIT decontamination to prevent fungal infection
-IV antibiotics for infection
-Blood transfusion if anemia and thrombocytopenia.

37. Cont: CNS: -neuroprophylaxis: Testis: Special consideration:
- meningeal infiltration:
Testis:
or chidectomy/radiotherapy if testis involvement.
by intrathecal chemotherapy, high dose systemic MTX or Aracytine. OR cerebrospinal irradiation

38. Prognosis in ALL parameters Good poor WBC low High(>50x10 9 /l)
Gender
Girls
Boys
Immunophenotype
C-ALL
B-ALL
Age
Child
Adult or infant.
Cytogenetic
Normal,hyperdiploid,
Ph+,11q23rearrangements.
Time to clear blast from blood
< 1week
>1week
Time to remission
<4weeks
>4weeks
Cns disease at presentation
Absent
Present
Minimal residual disease.
Negative at 1-3 months
Still positive at 3-6 months.

39. BM response to remission induction
Prognosis in AML
parameters
Favorable
unfavorable
Cytogentics
T(15;17).
T(8;21).
Inv(16).
Deletion of chromosome5or7.
11q23
T(6;9)
Abn(3q)complex rearrangments
BM response to remission induction
<5% blasts after first course
>20% blasts after first course.
age
<60yrs
>60yrs

40. Chronic lymphocytic leukemia (1)
Is characterised by the accumulation of nonproliferating mature-appearing lymphocytes in the blood, marrow, lymph nodes, and spleen
In most cases, the cells are monoclonal B lymphocytes that are CD5+
T cell CLL can occur rarely

41. CLINICAL Localized or generalized lymphadenopathy Petechiae Pallor
Splenomegaly (30-40% of cases)
Hepatomegaly (20% of cases)
Petechiae
Pallor

42. lymphadenopathy

43. Chronic lymphocytic leukemia

44. Hairy-cell leukemia

45. Smudge Cells

46. Smudge Cells

47. The diagnostic criteria for CLL
1) A peripheral blood lymphocyte count of greater than 5 G/L, with less than 55% of the cells being atypical
2) The cell should have the presence of Bcell-specific differentiation antigens (CD19, CD20, and CD24) and be CD5(+)
3) A bone marrow aspirates showing greater than 30% lymphocytes

48. Investigations
Pretreatment studies of patients with CLL should include examination of:
complete blood count
peripheral blood smear
reticulocyte count
Coomb’s test
renal and liver function tests
serum protein electrophoresis
immunoglobulin levels
plasma 2 microglobulin level
If available immunophenotyping should be carried out to confirm the diagnosis
Bone marrow biopsy and cytogenetic analysis is not routinely performed in CLL

49. Staging (1) Rai Classification for CLL 0 - lymphocytosis (>5 G/L)
I - lymphocytosis + lymphadenopathy
II - lymphocytosis + splenomegaly +/-lymphadenopathy
III - lymphocytosis + anemia (Hb <11g%) +/-lymphadenopathy or splenomegaly
IV - lymphocytosis + thrombocytophenia (Plt <100G/L) +/- anemia +/-lymphadenopathy +/- splenomegaly

50. Staging (2) Binet Classification for CLL
A. < 3 involved areas, Hb > 10g%, Plt > 100G/L
B. > 3 involved areas, Hb > 10g%, Plt > 100G/L
C. - any number of involved areas, Hb < 10g%,
Plt < 100G/L

51. Treatment
Treatment is reserved for patients with low- or intermediate risk disease who are symptomatic or have progressive disease (increasing organomegaly or lymphocyte doubling time of less than 12 months) and patients with high -risk disease
Alkylating agents (chlorambucil, cyclophosphamide)
Nucleoside analogs (cladribine, fludarabine)
Biological response modifiers
Monoclonal antibodies
Bone marrow transplantation
And systemic complications requiring therapy
antibiotics
immunoglobulin
steroids
blood products

52. Chronic myelogenous leukemia
(CML) is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells.

53. Leukemia Chronic Myelogenous Leukemia
Cancer of the granulocytes or monocytes, compared to leukocytes in lymphocytic leukemia
Comprises about 14% of all adult leukemias
Males slightly higher than females
One of the first cancers to have a specific genetic link to a chromosomal mutation identified for the disease
Philadelphia Chromosome

54. Pathophysiology Disorder of the stem cells in bone marrow
General infection fighting cells are the most harmed > granulocytes and monocytes (aka, neutrophils)
These immature cells take over the body’s mature neutrophils and hinder the body’s ability to fight infection properly
CML is caused by a genetic mutation with chromosomes 9 and 22 in the body
Abl on chromosome 9 is translocated to chromosome 22 and fuses with Bcr
This ABL-BCR protein is an unregulated tyrosine kinase and thus, is the source of the reproduction of immature granulocytes
Other functions include: upstream changes of DNA repair mechanisms, suppression of the body’s programmed cell death proteins, and changes in cytoskeletal structures

57. HEPATOSPLENOMEGALY

59. chronic phase
accelerated phase

60. accelerated phase
blast crisis

61. blast crisis

62. A small number of patients show some resistance to Imatanib
The BRC-ABL transcript has the ability to mutate and thus make imatinib ineffective
Imatinib binds to the closed conformation and BRC-ABL can mutate to the open conformation and thus makes imatanib ineffective
Two 2nd generation TKIs have proven to be more potent and are in trials to determine effectiveness against resistance to imatanib

63. Treatment Algorithm