Chronic Leukaemia

CHRONIC LEUKAEMIA

Sandesh Shrestha

1pharmacotherapeutics-ii

Introduction

Acte lymphoblastic leukaemiaAcute myeloblastic leukaemiaChronic lymphocytic leukaemiaChronic myelocytic leukaemia

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DefinitionChronic 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 chronicChronic 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 bedifferentiated from the other types of white blood

cellsbased 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 lossPhysical 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-agentrituximabAlemtuzumab 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 CMLSigns and Symptoms■ Fatigue■ Left upper quadrant pain■ Abdominal pain or distension■ Weight loss■ Night sweatsPhysical Examination■ Splenomegaly■ HepatomegalyLaboratory 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 chemotherapyConventional 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 effectand 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 GIside effects. Diarrhea is another common side effect that is doserelated and can be controlled with antidiarrheal medications. Doserelatededema and fluid retention often manifests as periorbital edema. Rarely, fluid retention can be severe, leading to pulmonaryand cerebral edema.


Bone marrow transplantationIn 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.


TYROSINE KINASE INHIBITORSDasatinib 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 wasFDA 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 formof bcr-abl that was FDA approved in 2007 for the treatment ofimatinib-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.


Interferon alfaPrior to the introduction of imatinib, IFN-α was the preferred

agentin 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.


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


Health & Medicine

Chronic Leukaemia