Presentation on Leukemia by Ms. Chinmayi Upadhyaya

Leukemia, were surviving is regarded as a victory, a disease that still acts as a risk factor among the folks of Hiroshima and Nagasaki, stays as one of the fields to be looked forward for the further research. The above presentation includes the topics to be covered during a presentation on Leukemia. Apt for the students of Pharmacology.

1. LEUKEMIA
By,
Chinmayi
Upadhyaya
1
st
M.Pharm
(Pharmacology)
1

2. OBJECTIVES:
•To define Leukemia.
•To understand the Etiology.
•To classify Leukemia.
•To understand the Pathophysiology .
•To be able to list the Symptoms.
•To understand the Pharmacotherapy.
2

3. WHAT IS LEUKEMIA?
Is a group of cancers that usually begins in
the Bone marrow and results in high
number of abnormal White Blood cells.

•No single causative agent
•Most from a combination of factors
–Genetic, environmental and infections.
3

4. 3.Infection:

i. Human T- cell Leukemia viruse type 1(HTLV-1).
ii. Human T- cell Leukemia viruse type 11
(HTLV-11).
1. Genetic factors:
2. Environmental
factors:
•Down’s syndrome.
•Bloom’s syndrome.
•Klinefelter’s syndrome.
•Wiskott- Aldrich’s syndrome.
•Fanconi’s anaemia.
•Ataxia telangiectasia.
•Ionising radiation.
•Chemical carcinogens.
•Certain drugs.
4

5. Classification of leukemias:
Based on cell types predominately involved and
on natural history of the disease:
–Acute lymphoblastic leukemia (ALL).
–Acute myelogenous leukemia (AML).
–Chronic myelogenous leukemia (CML).
–Chronic lymphocytic leukemia (CLL).
5

6. Myeloid vs. Lymphoid:
•Any disease that arises from the myeloid
elements (white blood cells) is a myeloid disease.
….. AML, CML

•Any disease that arises from the lymphoid
elements (T cell and B cell) is a lymphoid disease.
….. ALL, CLL
6

7. 1.1. Acute leukemiasAcute leukemias::
Immature cells (or “Blasts") proliferate rapidly
and begin to accumulate in various organs and
tissues.
• Sudden onset
• If left untreated is fatal within a few weeks or months
Types: Acute Myeloid Leukemia (AML)
Acute Lymphoblastic leukemia (ALL)
• B-cell Leukemias are more common than T-cell Leukemias.
Groups: Childhood (< 15 years) > 80% ALL
Adult (> 15 years) > 80% AML
Elderly (> 60 years)
7

8. 1.Acute Myeloid Leukemia:
PATHOPHYSIOLOGY :
•A single myeloblast accumulates genetic
changes which "freeze" the cell in its immature
state and prevent differentiation.
•when such a "differentiation arrest" is combined
with other mutations which disrupt genes
controlling proliferation, the result is the
uncontrolled growth of an immature clone of
cells, leading to the clinical entity of AML.
8

9. •The epigenetic induction of dedifferentiation by
genetic mutations that alter the function of
epigenetic enzymes, such as the DNA
demethylase, TET2 and the metabolic enzymes
IDH1 and IDH2,which lead to the generation of
a novel oncometabolite, D-2-
Hydroxyglutarate, which inhibits the activity of
epigenetic enzymes such as TET2.
•The hypothesis is that such epigenetic
mutations lead to the silencing of Tumor
supressor genes and/or the activation of proto-
oncogenes.
9

10. 10

11. Signs and Symptoms:
•A drop in red blood cell count (anemia) causes fatigue,
paleness, and shortness of breath.
•Lack of platelets can lead to easy bruising or bleeding with
minor Trauma.
•General symptoms include fever, fatigue, weight loss or loss of
appetite, Petechiae, bone and joint pain, and persistent or
frequent infections.
•Enlargement of the Spleen, Lymph node swelling. The skin is
involved about 10% of the time in the form of Leukemia cutis.
•Sweet's syndrome.
•Swelling of the Gums, Chloroma.
11

12. Diffusely swollen gums Chloroma
Petechiae Leukemia CutisSweet’s syndrome
12

13. TREATMENT
13

14. 1.Chemotherapy: i. Induction therapy:
•With Cytarabine and an Anthracycline
(Daunorubicin).
•"7+3” (or "3+7")= Cytarabine is given as a
continuous i.v. infusion for 7consecutive days
while the Anthracycline is given for 3 consecutive
days.
•Other alternative induction regimens, including
high-dose cytarabine alone or investigational
agents, may also be used.
•For very elderly patients options may include less
intense chemotherapy or palliative care.
14

15. a)Mechanism of action of Cytarabine:
•Inhibition of DNA replication in leukemic cells at
G1/S checkpoint leading to blockade of
progression of some Leukemic cells into
S phase.
•
Rapidly converts into cytosine Arabinoside
triphosphate, which damages DNA when
the cell cycle holds in the S phase(synthesis of
DNA).
15

16. •1.5- 3mg/kg. i.v. twice a day for 7days.
•Less than 10% of injected dose is excreted
unchanged in the urine in 12- 24 hrs.
•Only 20% of drug reaches the circulation in oral
administration.
16

17. Side effects:
•Cerebellar toxicity when given in high doses,
which may lead to Ataxia.
•Granulocytopenia and other impaired body
defenses, which may lead to infection and
Thrombocytopenia, which may lead
to Hemorrhage.
•Leukopenia, Anemia, GI disturbances,
Stomatitis, Conjunctivitis,
Pneumonitis, fever, and Dermatitis, Palmar-
plantarerythrodysesthesia
17

18. b)Mechanism of action of Daunorubicin:
•Interacts with DNA by intercalation and
inhibition of macromolecular biosynthesis. This
inhibits the progression of the
enzyme Topoisomerase II, which relaxes
supercoils in DNA for Transcription.
•Daunorubicin stabilizes the Topoisomerase II
complex after it has broken the DNA chain for
replication, preventing the DNA double helix
from being resealed and thereby stopping the
process of Replication.
•Maximum action in S phase but toxicity in G2
Phase.
18

19. •Intravenous infusion. Should not be
administered intramuscularly or
subcutaneously, since it may cause
extensive tissue necrosis.
•It should also never be
administered intrathecally (into the spinal
canal), as this will cause extensive damage
to the nervous system and may lead
to death.
19

20. Side effects:
•Sores in mouth and lips.
•Swelling of feet and lower legs.
•Cough, fever, irregular heartbeat,
•Hematologic: cause significant reduction in all
bone marrow celllines for 1-2 weeks after therapy.
Severe myelosuppression may result in
superinfection, hemorrhage, and/or death.
•Cardiovascular: Develop Heart failure.
•Dermatological: Alopecia, Urticaria,
Hyperpigmentation of skin and nails.
•GIT: Nausea, or vomiting, Diarrhea, Stomatitis.
•Local:Local tissue inflammation, Thrombophlebitis
and Necrosis.

20

21. Alopecia
Thrombophlebitis
Hyperpigmentation
21

22. ii. Consolidation:
Good-prognosis leukemias, will undergo an
additional 3 to 5 courses of intensive
chemotherapy.
• High risk of relapse, allogeneic stem cell
transplantation is usually recommended if
the patient is able to tolerate a transplant and
has a suitable donor.
22

23. Relapsed AML
•For patients with relapsed AML, the only
proven potentially curative therapy is a
hematopoietic stem cell transplant, if one
has not already been performed.
23

24. 2.Acute Lymphocytic Leukemia:
Pathophysiology:
•By damage to DNA that leads to uncontrolled cellular
growth and spreads throughout the body.
•Damage can be caused through the formation of
fusion genes, as well as the deregulation of a proto-
oncogene via juxtaposition of it to the promoter of
another gene, e.g. the T-cell receptor gene.
•This damage occurs naturally during mitosis or other
normal processes.
24

25. Signs and Symptoms:
•Laboratory tests that might show abnormalities in blood
count tests, renal function tests, electrolyte tests, and liver
enzyme tests.
•Generalized weakness and fatigue, Dizziness
•Anemia
•Frequent or unexplained fever and infection
•Weight loss and/or loss of appetite
•Excessive and unexplained bruising
•Bone pain, joint pain (caused by the spread of "blast" cells to
the surface of the bone or into the joint from the marrow
cavity)
•Breathlessness
•Enlarged lymph nodes, liver and/or spleen
•Pitting edema (swelling) in the lower limbs and/or abdomen
•Petechiae.
25

26. Treatment:
I.Chemotherapy: i. Induction therapy:
Combination of Prednisolone or
Dexamethasone, Vincristine, Asparaginase and
Daunorubicin is used to induce remission.
•Central nervous system prophylaxis can be
achieved via irradiation, Cytarabine or
liposomal Cytarabine.
26

27. a)Mechanism of action of Vincristine:
•Blocks cells in Mitosis.
•Binds to β Tubulin and blocks its ability to
polymerize with alpha-Tubulin into
microtubules.
•Metabolism occurs in liver and metabolites are
excreted in the bile.
•Intravenously administered.
•Elimination half life is 1-20hrs.
27

28. Side effects:
•Peripheral Neuropathy.
•Head ache, Jaw pain, Joint pain, Stomach
cramps, weakness, Hallucinations,
Unconsiousness.
•Skin rash
•Nausea and Vomiting.
28

29. b)Mechanism of action of Prednisolone:
Two hypothesis
Apoptosis is achieved via activation of death
receptors.(Fas & TNF receptor)
•Fas ligand(FasL) binds Fas & induces receptor
trimerization & the recruitment of Procaspase-8
via the adaptor protein(FADD)
•Upon autocatalysis & activation, Caspase-8
stimulates apoptosis.
•It directly cleaves & activates Caspase-3 & it
cleaves the proapoptotic Bcl-2 family
member(Bid).
29

30. •The proapoptotic Bcl-2 protein,Bax translocates
to the mitochondria in response to the death
stimuli promotes release of Cytochrome C.
•Truncated Bid(tBid) also translocates to
mitochondria upon activation by Caspase-8,
where it stimulates Cytochrome C release &
activation of Caspase-9.
•The subsequent activation of effector
Caspases, Caspase-3, Caspase-6 & Caspase-
7 leads to cleavage of cytoplasmic targets,
causing cell shrinkage,DNA fragmentation &
eventually apoptosis.
Repression of Transcription factor activity.
30

31. c)Mechanism of action of
Dexamethasone:
•The effect on lymphoid cells includes G1 phase
cell cycle arrest and apoptosis.
•Upregulation of Promyelocytic Leukemia
Protein(PML),its complex formation with Protein
kinaseB or Akt and a PML-dependent Akt
dephosphorylation.
oPML protein is involved in negative regulation of PI3K
signaling through dephosphorylation of Akt. PML
protein forms nuclear bodies or PML Oncogenic
Domains(POD). PML and PODs have been implicated
in the negative regulation of cell proliferation.31

32. •Multiple proapoptotic signals have been shown
to be dependent on PML, including caspase-
independent cell death.
•The main sideeffect is increased blood sugar
level and Bone thinning.
32

33. d)Mechanism of action of
Asparginase:
•The rationale behind asparaginase is that it takes
advantage of the fact that ALL leukemic cells and
some other suspected tumor cells are unable to
synthesize the non-essential amino acid asparagine,
whereas normal cells are able to make their own
asparagine
•Thus leukemic cells require high amount of
asparagine. These leukemic cells depend on
circulating asparagine. Asparaginase, however,
catalyzes the conversion of L-asparagine to aspartic
acid and ammonia. This deprives the leukemic cell of
circulating asparagine, which leads to cell death.
33

34. Symptoms:
•Hypersensitivity reaction.
•Coagulopathy.
•Bone marrow suppression is common but only mild to
moderate, rarely reaches clinical significance and
therapeutic consequences are rarely required.
• pancreatitis.
34

35. ii. Consolidation:
Use Vincristine, Cyclophosphamide, Cytarabine,
Daunorubicin, Etoposide, Thioguanine or
Mercaptopurine given as blocks in different
combinations.
35

36. a)Mechanism of action of Cyclophosphamide:
•Phosphoramide mustard introduce alkyl
radicals into DNA strands with interference with
DNA replication by forming DNA crosslinkage.
•Well absorbed orally.
Side effects:
•Urinary bladder toxicity.
•Myelodysplasia.
•Pulmonary fibrosis.
•Hypogammaglobulinemia.
•Opportunistic infection.
•Alopecia.
•Hyperpigmentation of the Skin.
36

37. b)Mechanism of action of Etoposide:
•Etoposide forms a ternary complex
with DNA and the topoisomerase II enzyme.
•It is given intravenously or orally in capsule
form. If the drug is given i.v., it must be done
slowly over a 30- 60min period because it can
lower blood pressure as it is being
administered. Blood pressure is checked often
during infusing, with the speed of administration
adjusted accordingly.
37

38. Side effects:
•Low blood pressure
•Hair loss
•Pain and or burning at the i.v.site
•Constipation or diarrhea
•Bone marrow suppression, leading to:
oAllergic-type reactions
oRash
oFever.
38

39. c)Mechanism of action of
Mercaptopurine:
•Converted in the body to corresponding
Monoribonucleotides, which inhibits the
conversion of Inosine monophosphate to
Adenine and Guanine nucleotides.
•Incomplete absorption through oral
administration(10-50%).
•Intravenous administration is preffered.
39

40. d)Mechanism of action of Thioguanine:
TGN are toxic to cells by:
Incorporation into DNA during the synthesis
phase(S-Phase) of the cell.
Through inhibition of the GTP-binding protein(G
protein) Rac1, which regulates the Rac
pathway.
Incooperation into RNA.
•Plasma half life is short.
•Excreted through Kidneys in Urine.
40

41. Side effects:
•Leukopenia & Neutropenia.
•Thrombocytopenia.
•Anemia.
•Anorexia.
•Nausea & Vomiting.
•Hepatotoxicity.
41

42. iii. Maintainance:
•With 6- Mercaptopurine. In some cases
combined with Vincristine and Prednisolone.
•Lasts for about 2 years.
42

43. II. Radiation therapy:
•Is used on painful bony areas, in high disease
burdens, or as part of the preparations for a bone
marrow transplant
•Whole-brain prophylaxis radiation used to be a
common method in treatment of children’s ALL.
•Recent studies showed that CNS chemotherapy
provided results as favorable but with less
developmental side-effects.As a result, the use of
whole-brain radiation has been more limited.
•Most specialists in adult leukemia have abandoned
the use of radiation therapy for CNS prophylaxis,
instead using intrathecal chemotherapy
43

44. III.Biological therapy:
•For relapsed ALL, aiming at biological targets
such as the proteasome, in combination with
chemotherapy, has given promising results in
clinical trials.
•In ongoing clinical trials, a CD19-CD3 bi-
specific Monoclonal Murine antibody,
Blinatumomab, is showing great promise.
44

45. 3.CHRONIC MYELOGENOUS
LEUKEMIA:
Pathophysiology:
•Chromosomal translocation.
•Transcription.
•Translation.
•Dimerization.
•Trans – phosphorylation.
•Activation of signaling cascade.
•Proliferation.
•Cell survival.
•Altered stromal layer.
•Expansion of leukemic cells in the bone marrow.
45

46. 46

47.  Asymptomatic (50% of patients)
 Fatigue
 Weight loss
 Abdominal fullness and anorexia
 Abdominal pain, esp splenic area
 Increased sweating
 Easy bruising or bleeding
 Splenomegaly (95%)
 Hepatomegaly (50%)
CLINICAL PRESENTAITON OF CMLCLINICAL PRESENTAITON OF CML
47

48. TREATMENT:
1) Control & prolong chronic phase (non-curative):
Bcr-Abl tyrosine-kinase inhibitors:
Imatinib, Dasatinib, Nilotinib and Radotinib:
•Imatinib inhibit the progression of CML in the
majority of patients (65–75%) .
•Dasatinib, blocks several further oncogenic
proteins, in addition to more potent inhibition of
the BCR-ABL protein.
• Nilotinib & Radotinib joined the class of novel
agents in the inhibition of the BCR-ABL protein.
48

49. Alpha- interferon:
•MOA is still unclear.Wheather it is because of
direct antiproliferative or apoptosis effects.
Chemotherapy:
•Drugs like Cytarabin is used.
49

50. 2)Eradicate malignant Clone (curative):
Allogeneic BM/stem cell transplantation:
•The only curative treatment for CML is a bone
marrow transplant or an Allogeneic stem cell
transplant.
50

51. 1V. CHRONIC LYMPHOCYTIC
LEUKEMIA:
Pathophysiology:
•Affects developing B-Lymphocytes. In people with
CLL, lymphocytes undergo a malignant change and
become Leukemic cells.
•The molecular pathogenesis is a complex, multistep
process leading to the replication of a malignant
clone of B-Lymphocytes. While some steps in this
pathway have been elucidated, many remain
unknown.
•
51

52. Signs and symptoms:
•Swollen lymph nodes (glands) in the neck, under
the arms or in the groin, due to collections of
lymphocytes in these areas,
•Pain or discomfort under the ribs on the left side,
due to an enlarged spleen,
•Anaemia, due to a lack of red cells, causing
persistent tiredness, dizziness, paleness, or
shortness of breath when physically active,
•Frequent or repeated infections and slow healing,
due to a lack of normal white blood cells,
•Increased or unexplained bleeding or bruising, due
to a very low platelet count,
•Excessive sweating at night,
•Unintentional weight loss.
52

53. Treatment:
•CLL is treated by chemotherapy, radiation
therapy, biological therapy, or bone marrow
transplantation.
•An initial treatment regimen that contains
Fludarabine and Cyclophosphamide has
demonstrated higher overall response rates
and complete response rates.
53

54. Mechanism of action ofFludarabine:
•It inhibits DNA synthesis.
•Several enzymes involved in DNA synthesis
are targets for inhibition.
•F-ara-ATP competes with normal
Deoxynucleotide, Deoxyadenosine Tri
phosphate(dATP), inhibiting directly DNA
polymerases.
•Inhibit DNA primase, Ribonucleotide reductase
•Together these actions inactivate completely
the DNA synthesis – Apoptosis.
54

55. •Administered intravenously.
•Half life is 10hrs.
•Renal excretion.
Side effects:
•Thrombocytopenia.
•Peripheral Neuropathy.
•Acute hemolytic Anemia.
•Pneumonitis,etc.
55

56. Hairy Cell Leukemia:
•Presence of mononuclear cells with hairy
cytoplasmic projections in the Bone marrow,
peripheral Blood and Spleen. Molecular
analysis of these cells assigned B-cell origin
expressing CD19, CD20 and CD22 antigen.
•Characterised clinically by the manifestations
due to Reticuloendothelial organs.
56

57. 57

58. Signs:
•Pancytopenia.
•Hairy cells in Blood and Bone marrow which
are positive for TRAP.
Treatment:
•Alpha-Interferon therapy.
•Splenectomy.
58

59. References:
1.KD Tripathi. Essentials of Medical Pharmacology.
Jaypee brothers Medical Publishers(P)LTD;6:820-
842.
2.Bruce Alberts, Alexander Johnson, Julian
Lewis,etal. Molecular Biology of the Cell. Garland
science,Taylor & Francis group of
Publications;5:1219-1232.
3.Goodman & Gilman. The Pharmacological basics
of Therapeutics. Medical publishing
division;11:1326-1345.
4.Harsh mohan.Text book of Pathology.Jaypee
brothers Medical Publishers(P)LTD;5:414-423.
5.Internet source.
59

60. THANK YOU
60