Rakesh Biswas MDRakesh Biswas MDProfessor, Medicine, People's Professor, Medicine, People's College of Medical Sciences, College of Medical Sciences,

Bhopal, IndiaBhopal, IndiaLecture first conceived and delivered to medicine Lecture first conceived and delivered to medicine undergrads in Melaka Manipal Medical College, undergrads in Melaka Manipal Medical College,

Manipal University, Melaka, Malaysia.Manipal University, Melaka, Malaysia.

Chronic Myeloid Leukemia

source:source:

http://leukemia.acor.org/storydir/landro.htmlhttp://leukemia.acor.org/storydir/landro.html

The clinical manifestations of The clinical manifestations of Chronic Chronic Myeloid Leukemia (Myeloid Leukemia (CML) are insidious CML) are insidious and are often discovered incidentally when and are often discovered incidentally when an elevated White Blood Cells (WBC) an elevated White Blood Cells (WBC) count is revealed by a routine blood count count is revealed by a routine blood count or when an enlarged spleen is revealed or when an enlarged spleen is revealed during a general physical examination.during a general physical examination.

Source: E-medicineSource: E-medicine

3 clinical phases3 clinical phases

1) 1) Initial chronic phaseInitial chronic phase

2) Accelerated phase2) Accelerated phase

3) Blast crisis3) Blast crisis

Most patients are diagnosed while still Most patients are diagnosed while still in the chronic phase.in the chronic phase.

Myelosuppressive therapy, was formerly the Myelosuppressive therapy, was formerly the mainstay of treatment mainstay of treatment

to convert a patient with CML from an to convert a patient with CML from an uncontrolled initial presentation uncontrolled initial presentation

to one with hematologic remission and to one with hematologic remission and normalization of the physical examination and normalization of the physical examination and laboratory findingslaboratory findings

Hydroxyurea (Hydrea), an inhibitor of Hydroxyurea (Hydrea), an inhibitor of deoxynucleotide synthesis, is the most deoxynucleotide synthesis, is the most common myelosuppressive agent used to common myelosuppressive agent used to achieve hematologic remission. achieve hematologic remission.

The initial blood cell count is monitored The initial blood cell count is monitored every 2-4 weeks, and the dose is adjusted every 2-4 weeks, and the dose is adjusted depending on the WBC and platelet counts.depending on the WBC and platelet counts.

CML accounts for 20% of all leukemias CML accounts for 20% of all leukemias affecting adultsaffecting adults

Increased incidence was reported among Increased incidence was reported among individuals exposed to radiation in Nagasaki individuals exposed to radiation in Nagasaki

and Hiroshima after the dropping of the and Hiroshima after the dropping of the atomic bomb.atomic bomb.

The presence of The presence of BCR/ABLBCR/ABL rearrangement rearrangement is the hallmark of CMLis the hallmark of CML,,

CML is an acquired abnormality that CML is an acquired abnormality that involves the hematopoietic stem cell. involves the hematopoietic stem cell.

It is characterized by a cytogenetic It is characterized by a cytogenetic aberration consisting of a reciprocal aberration consisting of a reciprocal translocation between the long arms of translocation between the long arms of chromosomes 22 and 9; t(9;22). chromosomes 22 and 9; t(9;22).

The translocation results in a shortened The translocation results in a shortened chromosome 22, chromosome 22,

an observation first described by Nowell and an observation first described by Nowell and Hungerford Hungerford

and subsequently termed the Philadelphia and subsequently termed the Philadelphia (Ph) chromosome after the city of discovery. (Ph) chromosome after the city of discovery.

The Philadelphia chromosomeThe Philadelphia chromosomeShown is the result of the reciprocal translocation Shown is the result of the reciprocal translocation

of 22q to the lower arm of 9 and 9q (c-of 22q to the lower arm of 9 and 9q (c-ablabl to a to a specific breakpoint cluster region [specific breakpoint cluster region [bcrbcr] of ] of chromosome 22 indicated by the arrows chromosome 22 indicated by the arrows

This translocation relocates an This translocation relocates an oncogene called oncogene called ablabl

from the long arm of from the long arm of chromosome 9 chromosome 9

to the long arm of chromosome to the long arm of chromosome 22 in the 22 in the BCRBCR region. region.

A new approach to treatment of this A new approach to treatment of this disease is to directly inhibit the disease is to directly inhibit the molecular cause of the disease.molecular cause of the disease.

…using a protein-tyrosine kinase …using a protein-tyrosine kinase inhibitor that inhibits the bcr-abl inhibitor that inhibits the bcr-abl tyrosine kinasetyrosine kinase

The 3-fold goals of treatmentThe 3-fold goals of treatment for CML for CML have changed markedly in the past 10 years; have changed markedly in the past 10 years;

a) Hematologic remission (normal CBC, no a) Hematologic remission (normal CBC, no organomegaly), organomegaly),

b) Cytogenetic remission (normal chromosome b) Cytogenetic remission (normal chromosome 0% Ph-positive cells), and, most recently, 0% Ph-positive cells), and, most recently,

c) Molecular remission (negative PCR result for c) Molecular remission (negative PCR result for the mutational the mutational BCR/ABLBCR/ABL m-RNA). m-RNA).

The latter is an attempt for cure and prolongation of patient The latter is an attempt for cure and prolongation of patient survival.survival.