Chronic Leukaemia

CHRONIC LEUKAEMIA
Sandesh Shrestha
1pharmacotherapeutics-ii

Introduction
Acte lymphoblastic leukaemia
Acute myeloblastic leukaemia
Chronic lymphocytic leukaemia
Chronic myelocytic leukaemia
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Definition
Chronic leukemia is a disease in which clonal expasion of
white blood cells are takes place in the bone marrow.
Depending on the type of white blood cell that is involved,
chronic leukemia can be classified as
- chronic lymphocytic leukemia
- chronic myelocytic leukemia.

The two types of chronic
Chronic lymphocytic leukemia (CLL) involves
the T or B lymphocytes. B cell
abnormalities are more common than T
cell abnormalities.
T cells are affected in only 5% of the
patients.
The T and B lymphocytes can be
differentiated from the other types of white
blood cells
based on their size and by the absence of
granules inside them.
In chronic myelogenous leukemia (CML), the
cells that are affected are the
granulocytes.

Etiology
- No particular etiological factor is found but
exposure to ionizing radiation and to
certain
- organic chemicals, such as benzene.
- Chronic leukemia -retroviruses (HTLV-I
and HTLV-II).
- Haematological disorders- aplastic
anaemia
non leukaemic myeloproliferative disorder
-Genetical – downs syndrome, fanconi
anaemia

Epidemiology
-Chronic leukemias account for 1.2% of all cancers.
-leukemias affect nine times as many adults as
children.
-In chronic lymphoid leukemia, 90% of the cases are
seen in people who are 50 years or older, with the
average age at diagnosis being 65.
-The incidence of the disease increases with age. It is
almost never seen in children.
-Chronic myeloid leukemias are generally seen in
people in their mid-40s. It accounts for about 4% of
childhood
leukemia cases.
-According to the estimates of the American Cancer
Society (ACS), approximately 29,000 new cases of
leukemia will be diagnosed in 1998.

Diagnosis
• By physical examination-lymphadinopathy
liver and spleen enlarged
• Blood tests; results may need to be
confirmed with a bone marrow biopsy
• Flow cytometry (immunophenotyping):
cancer cells are treated with chemicals or
dyes that enhance distinctive traits on their
surface
• X-ray
• Computed tomography (CT ) scan

Chronic lymphocytic leukaemia
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Pathophysiology
Clonal expansion of morphologically mature
lymphocytes(B cell origin)
The cells accumulate in peripheral blood and
gives rise to a lymphocytosis
Lymphocytes accumulate in lymph nodes
and spread to the liver and spleen which
become enlarged.

CLINICAL PRESENTATION
Symptoms
Fever, fatigue, weight loss
Physical Examination
■ Lymphadenopathy (87%)
■ Splenomegaly (54%)
■ Hepatomegaly (14%)
Laboratory Tests
■ Peripheral blood
• Lymphocytosis
• Anemia
• Thrombocytopenia
■ Bone marrow
• Hypercellular
• Increased mature lymphocytes

CLL Staging
• Staging is a way of describing a cancer,
such as where it is located, if or where it
has spread, and if it is affecting the
functions of other organs in the body
• Staging is an important tool to determine
the likelihood that the disease may worsen
and require treatment
• The Rai staging system divides CLL into
different stages ranging from 0 (zero) to
IV (four)

staging
• 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 + thrombocytopenia
(Plt <100G/L) +/- anemia +/-
lymphadenopathy +/- splenomegaly

Cot….
• (european staging system)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

Risk Groups of CLL
• Sometimes the phrase “risk group” is used
to express the likelihood that the disease
may worsen and require treatment
• There are three risk groups:
• Low risk: stage 0
• Intermediate risk: stages I and II
• High risk: Rai stages and IV

Treatement
• Chemotherapy
• Monoclonal antibodies
• Radiation therapy
• More than one treatment may be used

Chemotherapy
• Use of drugs to kill cancer cells
• Chemotherapy may be given orally,
intravenously (IV)
• Typical medications include fludarabine,
pentostatin , cladribine , chlorambucil ,
cyclophosphamide
• Orally administered alkylating agents such
as chlorambucil and cyclophosphamide
can be used dose-15 to 40 mg/m2 orally
every 28 days or daily doses of 4 to 8
mg/m2 per day.

Cont…
• Chlorambucil intolerated patients-
Cyclophosphamide is typically given orally at a
daily dose of 1 to 3 mg/kg
• Fludarabine is particularly useful in
youngerpatients and in those patients who can
tolerate immunosuppressive chemotherapy.
• Fludarabine, along with the other purine analogs,
(cladribine) and (pentostatin), is highly active in
CLL, with fludarabine being the most widely studied
purine analog in the treatment of CLL.
Dose-fludarabine 20 mg/m2 intravenously daily
for 5 days when used as
single-agent chemotherapy.

Monoclonal Antibodies or biologic therapy
• Substances that support or stimulate the body’s
immune system to fight cancer
• who had been treated with alkylating agents and
had failed fludarabine therapy.
• Rituximab can be used for B-cell CLL
The guidelines do not recommend single-agent
rituximab
Alemtuzumab a monoclonal antibody approved for
use by the U.S. Food and Drug Administration
(FDA) for treatment of advanced CLL after other
treatments fail. It is used in both B-cell and T-cell
CLL
dose of 30 mg intravenously given three times a week
for 12 weeks.

Combination therapy-
• Results from an uncontrolled trial of fludarabine,
cyclophosphamide, and rituximab reported a
complete remission rate of 70% in previously
untreated CLL patients
• combination of fludarabine and alemtuzumab
achieved an overall response rate of 83% in
heavily pretreated patients.
• Combinations of alemtuzumab and rituximab
produced a response rate of 53% in a group of CLL
patients. The response rates were higher (63%) in
• patients who had not received prior antibody
therapy

Radiation Therapy
The use of high-energy x-rays to destroy
cancer cells
External beam: outside the body Usually
given to shrink an enlarged spleen or
swollen lymph nodes and eliminate
symptoms associated with such growths
Side effects can include fatigue, mild skin
reactions, nausea, diarrhea, or
constipation

Supportive Treatment for CLL
• Used to control or treat symptoms (either
from CLL or its treatment)
• Blood transfusions
• Antibiotics to treat infection
• Immunoglobulin infusion for people with
recurrent infections
• Splenectomy (surgery used to remove an
enlarged spleen)

Chronic myelocytic leukaemia
(chronic myelogenous leukemia, chronic granulocytic leukemia)

CML is a myeloproliferative disease that results from a
malignant transformation of an early hematopoietic
progenitor cell. This leads to abnormal proliferation and
accumulation of progenitor and mature myeloid cells in
the bone marrow and peripheral blood.
• The clinical course of CML has three phases:
chronic phase
accelerated phase
blast crisis.
-The disease begins in the chronic phase in which signs and
symptoms can be controlled with chemotherapy.
-CML then progresses to a transition phase, known as
accelerated phase, in which blast counts in the bone
marrow and peripheral blood increase despite ongoing
therapy.
- Finally, there is blast crisis, a terminal phase that is similar
to acute leukemia that can lead to rapid clinical
deterioration and death.

CLINICAL PRESENTATION OF CML
Signs and Symptoms
■ Fatigue
■ Left upper quadrant pain
■ Abdominal pain or distension
■ Weight loss
■ Night sweats
Physical Examination
■ Splenomegaly
■ Hepatomegaly
Laboratory Tests
■ Peripheral blood
• Leukocytosis
• Thrombocytosis
• Basophilia
■ Molecular testing
• Presence of bcr-abl by reverse-transcription polymerase chain
reaction
■ Bone marrow
• Hypercellular
• Fully mature myeloid cells
■ Cytogenetics
• Presence of the Ph chromosome

TREATMENT
• Different treatment options are available
for patients with CML.
• conventional treatment
• Bone marrow transplantation,
• radiation therapy,
• biologic therapy, or a combination of these
approaches are used.

Conventional chemotherapy
Conventional cytotoxic chemotherapy can be used in
chronic-phase the two agents used are busulfan
and hydroxyurea . Busulfan is rarely used because
randomized trials show that hydroxyurea treatment
provides a significant survival advantage over
busulfan.
• Hydroxyurea - The drug is usually administered
daily and can be initiated at
• 40 to 50 mg/kg/day in divided doses until the WBC
count falls below 10,000 cells/mm3. At this point,
the dose can be decreased to a
• maintenance level of 20 mg/kg/day

Imatinib
CCR, complete cytogenetic response; CML, chronic myelogenous leukemia;
CML-AP, accelerated phase;
CML-BC, blast crisis; CML-CP, chronic phase;
MCR, major cytogenetic response.
Dose-related nausea and vomiting is the
most common side effect
and can be managed by taking the drug
with a meal.
Higher doses of imatinib should be split in
half and taken twice daily to reduce GI
side effects.
Diarrhea is another common side effect
that is doserelated and can be controlled
with antidiarrheal medications. Doserelated
edema and fluid retention often manifests
as periorbital edema. Rarely, fluid retention
can be severe, leading to pulmonary
and cerebral edema.

Bone marrow transplantation
In BMT, the patient’s diseased bone marrow is
replaced with healthy marrow.
There are two ways of doing a bone marrow
transplant.
In an allogeneic bone marrow transplant, healthy
marrow is taken from another person (donor)
whose tissue is either the same or very closely
resembles the patient’s tissues.
First, the patient’s bone marrow is destroyed with very
high doses of chemotherapy and radiation therapy.
To replace the destroyed marrow, healthy marrow
from the donor is given to the patient through a
needle in the vein. 31pharmacotherapeutics-ii

TYROSINE KINASE INHIBITORS
Dasatinib and nilotinib are two recently approved tyrosine
kinase inhibitors used to overcome resistance in CML.
Dasatinib is an oral bcr-abl tyrosine kinase inhibitor that was
FDA approved in 2006 for the treatment of imatinib-resistant
CML.
Unlike imatinib, dasatinib binds to both the active and
inactive forms of bcr-abl kinase and can overcome most
bcr-abl mutations responsible for imatinib resistance.
DOSE - 70 mg twice daily or 100 mg once daily
Nilotinib is an oral tyrosine kinase inhibitor of the inactive
form
of bcr-abl that was FDA approved in 2007 for the treatment
of
imatinib-resistant CML.
Nilotinib is 10 to 30 times more potent in inhibiting bcr-abl
than imatinib
Dose - 400 mg twice daily;
400 to 600 mg twice daily for imatinib-resistant
CML.
32
pharmacotherapeutics-ii

Interferon alfa
Prior to the introduction of imatinib, IFN-α was the preferred
agent
in the treatment of CML. Today it is reserved for patients
who fail tyrosine kinase inhibitor therapie.
The interferons are a family of glycoproteins involved in
many of the functional aspects of the hematopoietic
system.
Two recombinant forms of IFN-α are currently marketed:
IFN-α2a and IFN-α2b .
In addition, two polyethylene glycolconjugated products were
developed in an attempt to improve the toxicity profile
and decrease the frequency of injections of IFN-α
(PEG-IFN-α2b and PEG-IFN-α2a).
PEG-IFN-α2b can be administered weekly as
compared with daily administration

Cont….
In the second type of bone marrow transplant, called
an autologous bone marrow transplant, some of
the patient’s own marrow is taken out and treated
with a combination of anticancer drugs to kill all
the abnormal cells.
This marrow is then frozen to save it. The marrow
remaining in the patient’s body is then destroyed
with high dose chemotherapy and radiation
therapy.
Following that, the patient’s own marrow that was
frozen is thawed and given back to the patient
through a needle in the vein. This mode of bone
marrow transplant is currently being investigated in
clinical trials.
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References
-Gale encyclopedia of medicine, vol-3 , (G-
M), pg no 1991-1992.
- Clinical pharmacy and therapeutics, roser
walker, 4 th edition, pg no-715-718.
- Pharmacotherapy , a pahologic approach,
joseph.T. dipiro , 7 th edition, pg no 2281-
2291.
-Harrison’s internal medicine, 17 th edition.
-Chronic Myeloid Leukemia,Salwa Hassan
Teama,M.D. N.C.I. Cairo University, Egypt

Chronic Leukaemia

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