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Chronic Myelogenous leukemia (CML)

Updated : April 26, 2024





Background

Chronic myelogenous leukemia is a blood cancer that attacks the bone marrow as well. It is essentially a condition when there is accumulation of white blood cells (granulocytes) in the bone marrow. Abnormal white blood cells which are usually designated as leukemia cells or blast cells are frequently the primary cause of leukemia diseases. Human chromosomes have different roles and their abnormality involves a random exchange of parts between chromosomes 9 and 22. Therefore this gene mutation results in the detection of the BCR-ABL1 fusion gene which codes for a protein that stimulates the cell to grow and divide most irregularly. The infection is usually gradual and normally the first signs are not manifest until the disease is in its advanced stage. 

Epidemiology

The incidence of CML globally is 0.87 cases/100,000 people which is almost the same for all ages but the peak of it was at the age of 70 and older where it reached 1.52 cases/100,000 people of that age. Besides that the disease higher chance of happening in males compared to females. The statistical centre of age at diagnosis is 56 years. 

Anatomy

Pathophysiology

Philadelphia Chromosome Formation: The chromosome 9 and 22 were phased in over 95% of CML cases. This phenomenon is called the Philadelphia chromosome which is the cause for this genetic anomaly. As a result the BCR-ABL gene is made up.  

BCR-ABL Oncogene: The gene forms an abnormally active protein called “TYK2”, which causes a cell signalling pathway that stimulates the cell growth and survival activities. 

Abnormal Myeloid Cell Growth: By this oncogene’s intervention the normal myeloid cells and granulocytes‘ development into mature cells in the bone marrow is ceased and, in their place, the immature leukocytes rapidly proliferate resulting in a high white blood cell count. 

Inhibition of Differentiation and Apoptosis: The fusion of protein prevents myeloid cells from maturing and the buildup of immature cells. It is also responsible for cell death prevention and thus the persistence and multiplication of abnormal cells. 

Clinical Manifestations: Among the earliest symptoms are tiredness weight loss, fever and abdominal pain from enlarged spleen and the lowered ability to fight off infections because of impaired immunity. 

Etiology

Chronic Myelogenous Leukaemia is a consequence of the cytogenetic abnormality called Philadelphia chromosome. This chromosome features a translocation between the distinct chromosomes 9 and 22 and by doing so it generates a fusion gene called BCR-ABL. This unusual gene produces a protein that acts to stimulate cell division without being able to prevent them from growing out of control and this is what leads to CML. 

Genetics

Prognostic Factors

Cytogenetic Abnormalities: Specific genetic perversities e.g. the Philadelphia chromosome play their roles in CML and different additional chromosomal abnormalities correlate with worse outcomes in CML.  

Blast Crisis Transformation: As to CML development a subsequent crisis may result in an increased number of immature cells (blasts). It shall be related to a worse outcome. 

Response to Treatment: Patient responses to the treatment and most importantly so with tyrosine kinase inhibitors is significantly important in determining the prognosis. 

Clinical History

Age group: Although people of any age might be affected by CML, adults are the ones who are often diagnosed with the disease with an average age of 64.  

Physical Examination

General Appearance 

Skin assessment 

Lymph Nodes examination 

Spleen and Liver assessment 

Cardiovascular assessment 

Respiratory assessment 

Neurological Examination 

Age group

Associated comorbidity

Cardiovascular disease 

Thrombosis 

Anemia 

Gastrointestinal symptoms 

Psychological distress 

Associated activity

Acuity of presentation

Unintentional Weight Loss: People with CML may lose weight accidentally and without attempting to.  

Abdominal pain: CML patients may experience splenomegaly or enlarged spleen and less frequently hepatomegaly or enlarged liver which can cause pain or fullness in the belly. 

Fatigue: This is also the common symptoms associated with CML. 

Differential Diagnoses

Acute Myeloid Leukemia 

Other Myeloproliferative Neoplasms 

Reactive Causes of Leukocytosis 

Benign Leukocytosis 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

Tyrosine kinase inhibitors: TKIs are essential for treating chronic myeloid leukemia because they work by blocking the BCR-ABL protein.
Allogeneic Stem Cell Transplantation: When a patient has advanced CML or is resistant to several TKIs stem cells from a healthy donor are used to replace the diseased bone marrow. 

Clinical Trials: For patients whose traditional treatments are unsuccessful or who would like access to innovative medications clinical trials investigate new CML treatments such as targeted therapy and therapeutic combinations. 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

Lifestyle modifications in treating CML

Reduce Toxin Exposure: To reduce the burden on your immune system, stay away from pesticides and smoking.  

Keep It clean: To improve air quality and lower allergies keep your area neat and free of mould and dust. 

Handle Stress: Reduce stress which can impair your immune system by including calming methods like yoga or meditation. 

Remain Active: To improve your mood immunity and general well-being do light to moderate exercise daily. 

Effectiveness of antineoplastics agents in treating CML

Hydroxyurea: Hydroxyurea acts by blocking the ribonucleotide reductase enzyme which is useful in producing DNA. 

Busulfan: It acts as an alkylating agent which prevents the cell division and inhibits DNA synthesis.  

3- Role of Tyrosine Kinase Inhibitors in treating CML: Specialty: Hematology 

Imatinib: The first TKI authorised for the treatment of CML was imatinib. Particularly during the chronic stage of the illness it has proven to be quite successful.  

Bosutinib: Patients with CML who are resistant to, or intolerant of previous therapy may be treated with bosutinib a TKI. 

Role of FGFR Inhibitors in treating CML

Pemigatinib is a medication for adults with refractory/relapsed cholangiocarcinoma that inhibits FGFR 1/2/3 phosphorylation and reducing cell viability in cancer cell lines. 

Role of management in treating CML

Diagnosis: CML is diagnosed through blood tests like CBC and bone marrow biopsy, often confirmed with molecular tests like PCR or FISH for the Ph chromosome. 

Initial treatment: It includes tyrosine kinase inhibitors such as imatinib, dasatinib and bosutinib. These are chosen based on factors like age and health to reduce abnormal white blood cells and halt disease progression.  

Monitoring: It involves regular tests like blood cell counts and quantitative PCR and occasionally bone marrow biopsies to track treatment response and disease progression. 

Long-Term Management: Patients with good treatment responses continue TKI therapy and undergo regular monitoring for disease recurrence or progression. 

Medication

 

dasatinib

100

mg

Tablet

Oral

once a day



nilotinib

It is used for the treatment of newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase Ph+ CML-CP:

300

mg

Orally

twice a day



imatinib

400 mg given orally per day for chronic phase   
600 mg given orally per day for accelerated phase or blast crisis   
An increased dose is given to patients if there is no severe adverse drug reaction or severe non-leukemia as in the below areas:   
the disease progression fails to reach satisfactory hematologic response after at least three months of treatment, failure to achieve a cytogenetic response after 6-12 months of treatment or loss of a previously completed hematologic or cytogenetic response   
600 mg orally once a day for disease progression chronic phase    400 mg orally two times a day for disease progression accelerated phase or blast crisis    continue the treatment until there is no progressive disease or unacceptable toxicity occurs   



bosutinib

Take a dose of 400 mg orally once daily:



ponatinib 

ponatinib is indicated to treat chronic myeloid leukemia
A dose of 45 mg, four times daily, is administered four times daily
The medication is continued until the disease is reduced to acceptable toxicity
Discontinue treatment if the response doesn’t occur after three months



omacetaxine 

Induction: 1.25 mg/m2 Subcutaneous twice a day for 2 weeks every 28 days; continue every 28 days till the hematologic response is achieved.
maintenance: 1.25 mg/m2 Subcutaneous twice a day for 1 week every 28 days; continue for as long as clinically necessary



Dose Adjustments

Dosing Modifications
Nonhematologic toxicity should be managed symptomatically; therapy may be interrupted and/or delayed until the toxicity is resolved
Thrombocytopenia or neutropenia
For hematologic toxicities (e.g., thrombocytopenia, neutropenia), dosage cycles can be delayed or the total number of days throughout the cycle reduced
Grade 3 thrombocytopenia (platelets below 50 x 109/L) or grade 4 neutropenia (AND below 0.5 x 109/L) Delay initiating the next cycle till the ANC and platelet counts are above 1 and 50 x 109/L, respectively
Reduce the number of dosage days by two days for the next cycle (for example 12 or 5 days)

asciminib 


Indicated for Chronic Myeloid Leukemia
Patients with the T3151 mutation:
200 mg orally two times a day
Continue until unacceptable toxicity or the disease progression occurs Prior treated patients: 80 mg orally every day
Or
40 mg orally two times a day
Continue until unacceptable toxicity or the disease progression occurs
Dose modifications
For adverse reactions, dose reductions:
1st dose diminishment
Prior treated Ph+ CP-CML: 40 mg orally every day
Or
20 mg orally two times a day
Ph+ CP-CML with the T3151 mutation: 160 mg orally two times a day
For patients who are unable to tolerate 1st dose diminishment, permanently discontinue
Thrombocytopenia or neutropenia:
Retain until the ANC is more than 1x 109/L or the platelets are more than 50x 109/L
Resolved within 2 weeks: Restart at the starting dose
Resolved >2 weeks: Restart at a decreased dose
If it reoccurs, restain until the ANC is more than 1x 109/L or the platelets are more than 50x 109/L; then restart at a reduced dose
Asymptomatic amylase or lipase elevation
Retain until the <1.5x ULN occurs
If resolved, restart at a decreased dose
If not resolved, discontinue permanently
If it reoccurs at decreased dose, discontinue permanently
Renal impairment
Mild-severe: Dose adjustment not necessary
Hepatic impairment
Mild-severe: Dose adjustment not necessary



hydroxycarbamide 

A single oral dose of 20 to 30 mg/kg/day. As an alternative, administer 80 mg/kg as a single dose every three days (for solid tumours). Concomitant irradiation treatment: 80 mg/kg as a single dosage given every three days, starting at least 1 week before radiotherapy, is considered



 

nilotinib

For > 1year children
230 mg per m2 orally 2x a day
and round to the nearest 50 mg dose
the Maximum dose given is 400 mg per dose
Dosing based on body surface area (BSA):
if BSA 0.32 m2: 50 mg orally 2x a day
if BSA 0.33-0.54 m2: 100 mg orally 2x a day
if BSA 0.55-0.76 m2: 150 mg orally 2x a day
if BSA 0.77-0.97 m2: 200 mg orally 2x a day
if BSA 0.98-1.19 m2: 250 mg orally 2x a day
if BSA 1.2-1.41 m2: 300 mg orally 2x a day
if BSA 1.42-1.63 m2: 350 mg orally 2x a day
if BSA 1.64 m2: 400 mg orally 2x a day



imatinib

Age:>1 year   
340 mg per m2 given orally per day or 170 mg per m2 given orally twice a day   
The maximum dose given is 600 mg daily   
continue the treatment until there is no progressive disease or unacceptable toxicity occurs  
Age: <1year   
Safety and efficacy not established   



bosutinib

Safety and efficacy not established



 

bosutinib

Refer adult dosing



Media Gallary

References

Chronic Myelogenous Leukemia – StatPearls – NCBI Bookshelf (nih.gov) 

 

Chronic Myelogenous leukemia (CML)

Updated : April 26, 2024




Chronic myelogenous leukemia is a blood cancer that attacks the bone marrow as well. It is essentially a condition when there is accumulation of white blood cells (granulocytes) in the bone marrow. Abnormal white blood cells which are usually designated as leukemia cells or blast cells are frequently the primary cause of leukemia diseases. Human chromosomes have different roles and their abnormality involves a random exchange of parts between chromosomes 9 and 22. Therefore this gene mutation results in the detection of the BCR-ABL1 fusion gene which codes for a protein that stimulates the cell to grow and divide most irregularly. The infection is usually gradual and normally the first signs are not manifest until the disease is in its advanced stage. 

The incidence of CML globally is 0.87 cases/100,000 people which is almost the same for all ages but the peak of it was at the age of 70 and older where it reached 1.52 cases/100,000 people of that age. Besides that the disease higher chance of happening in males compared to females. The statistical centre of age at diagnosis is 56 years. 

Philadelphia Chromosome Formation: The chromosome 9 and 22 were phased in over 95% of CML cases. This phenomenon is called the Philadelphia chromosome which is the cause for this genetic anomaly. As a result the BCR-ABL gene is made up.  

BCR-ABL Oncogene: The gene forms an abnormally active protein called “TYK2”, which causes a cell signalling pathway that stimulates the cell growth and survival activities. 

Abnormal Myeloid Cell Growth: By this oncogene’s intervention the normal myeloid cells and granulocytes‘ development into mature cells in the bone marrow is ceased and, in their place, the immature leukocytes rapidly proliferate resulting in a high white blood cell count. 

Inhibition of Differentiation and Apoptosis: The fusion of protein prevents myeloid cells from maturing and the buildup of immature cells. It is also responsible for cell death prevention and thus the persistence and multiplication of abnormal cells. 

Clinical Manifestations: Among the earliest symptoms are tiredness weight loss, fever and abdominal pain from enlarged spleen and the lowered ability to fight off infections because of impaired immunity. 

Chronic Myelogenous Leukaemia is a consequence of the cytogenetic abnormality called Philadelphia chromosome. This chromosome features a translocation between the distinct chromosomes 9 and 22 and by doing so it generates a fusion gene called BCR-ABL. This unusual gene produces a protein that acts to stimulate cell division without being able to prevent them from growing out of control and this is what leads to CML. 

Cytogenetic Abnormalities: Specific genetic perversities e.g. the Philadelphia chromosome play their roles in CML and different additional chromosomal abnormalities correlate with worse outcomes in CML.  

Blast Crisis Transformation: As to CML development a subsequent crisis may result in an increased number of immature cells (blasts). It shall be related to a worse outcome. 

Response to Treatment: Patient responses to the treatment and most importantly so with tyrosine kinase inhibitors is significantly important in determining the prognosis. 

Age group: Although people of any age might be affected by CML, adults are the ones who are often diagnosed with the disease with an average age of 64.  

General Appearance 

Skin assessment 

Lymph Nodes examination 

Spleen and Liver assessment 

Cardiovascular assessment 

Respiratory assessment 

Neurological Examination 

Cardiovascular disease 

Thrombosis 

Anemia 

Gastrointestinal symptoms 

Psychological distress 

Unintentional Weight Loss: People with CML may lose weight accidentally and without attempting to.  

Abdominal pain: CML patients may experience splenomegaly or enlarged spleen and less frequently hepatomegaly or enlarged liver which can cause pain or fullness in the belly. 

Fatigue: This is also the common symptoms associated with CML. 

Acute Myeloid Leukemia 

Other Myeloproliferative Neoplasms 

Reactive Causes of Leukocytosis 

Benign Leukocytosis 

Tyrosine kinase inhibitors: TKIs are essential for treating chronic myeloid leukemia because they work by blocking the BCR-ABL protein.
Allogeneic Stem Cell Transplantation: When a patient has advanced CML or is resistant to several TKIs stem cells from a healthy donor are used to replace the diseased bone marrow. 

Clinical Trials: For patients whose traditional treatments are unsuccessful or who would like access to innovative medications clinical trials investigate new CML treatments such as targeted therapy and therapeutic combinations. 

Reduce Toxin Exposure: To reduce the burden on your immune system, stay away from pesticides and smoking.  

Keep It clean: To improve air quality and lower allergies keep your area neat and free of mould and dust. 

Handle Stress: Reduce stress which can impair your immune system by including calming methods like yoga or meditation. 

Remain Active: To improve your mood immunity and general well-being do light to moderate exercise daily. 

Hydroxyurea: Hydroxyurea acts by blocking the ribonucleotide reductase enzyme which is useful in producing DNA. 

Busulfan: It acts as an alkylating agent which prevents the cell division and inhibits DNA synthesis.  

3- Role of Tyrosine Kinase Inhibitors in treating CML: Specialty: Hematology 

Imatinib: The first TKI authorised for the treatment of CML was imatinib. Particularly during the chronic stage of the illness it has proven to be quite successful.  

Bosutinib: Patients with CML who are resistant to, or intolerant of previous therapy may be treated with bosutinib a TKI. 

Pemigatinib is a medication for adults with refractory/relapsed cholangiocarcinoma that inhibits FGFR 1/2/3 phosphorylation and reducing cell viability in cancer cell lines. 

Diagnosis: CML is diagnosed through blood tests like CBC and bone marrow biopsy, often confirmed with molecular tests like PCR or FISH for the Ph chromosome. 

Initial treatment: It includes tyrosine kinase inhibitors such as imatinib, dasatinib and bosutinib. These are chosen based on factors like age and health to reduce abnormal white blood cells and halt disease progression.  

Monitoring: It involves regular tests like blood cell counts and quantitative PCR and occasionally bone marrow biopsies to track treatment response and disease progression. 

Long-Term Management: Patients with good treatment responses continue TKI therapy and undergo regular monitoring for disease recurrence or progression. 

dasatinib

100

mg

Tablet

Oral

once a day



nilotinib

It is used for the treatment of newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase Ph+ CML-CP:

300

mg

Orally

twice a day



imatinib

400 mg given orally per day for chronic phase   
600 mg given orally per day for accelerated phase or blast crisis   
An increased dose is given to patients if there is no severe adverse drug reaction or severe non-leukemia as in the below areas:   
the disease progression fails to reach satisfactory hematologic response after at least three months of treatment, failure to achieve a cytogenetic response after 6-12 months of treatment or loss of a previously completed hematologic or cytogenetic response   
600 mg orally once a day for disease progression chronic phase    400 mg orally two times a day for disease progression accelerated phase or blast crisis    continue the treatment until there is no progressive disease or unacceptable toxicity occurs   



bosutinib

Take a dose of 400 mg orally once daily:



ponatinib 

ponatinib is indicated to treat chronic myeloid leukemia
A dose of 45 mg, four times daily, is administered four times daily
The medication is continued until the disease is reduced to acceptable toxicity
Discontinue treatment if the response doesn’t occur after three months



omacetaxine 

Induction: 1.25 mg/m2 Subcutaneous twice a day for 2 weeks every 28 days; continue every 28 days till the hematologic response is achieved.
maintenance: 1.25 mg/m2 Subcutaneous twice a day for 1 week every 28 days; continue for as long as clinically necessary



Dose Adjustments

Dosing Modifications
Nonhematologic toxicity should be managed symptomatically; therapy may be interrupted and/or delayed until the toxicity is resolved
Thrombocytopenia or neutropenia
For hematologic toxicities (e.g., thrombocytopenia, neutropenia), dosage cycles can be delayed or the total number of days throughout the cycle reduced
Grade 3 thrombocytopenia (platelets below 50 x 109/L) or grade 4 neutropenia (AND below 0.5 x 109/L) Delay initiating the next cycle till the ANC and platelet counts are above 1 and 50 x 109/L, respectively
Reduce the number of dosage days by two days for the next cycle (for example 12 or 5 days)

asciminib 


Indicated for Chronic Myeloid Leukemia
Patients with the T3151 mutation:
200 mg orally two times a day
Continue until unacceptable toxicity or the disease progression occurs Prior treated patients: 80 mg orally every day
Or
40 mg orally two times a day
Continue until unacceptable toxicity or the disease progression occurs
Dose modifications
For adverse reactions, dose reductions:
1st dose diminishment
Prior treated Ph+ CP-CML: 40 mg orally every day
Or
20 mg orally two times a day
Ph+ CP-CML with the T3151 mutation: 160 mg orally two times a day
For patients who are unable to tolerate 1st dose diminishment, permanently discontinue
Thrombocytopenia or neutropenia:
Retain until the ANC is more than 1x 109/L or the platelets are more than 50x 109/L
Resolved within 2 weeks: Restart at the starting dose
Resolved >2 weeks: Restart at a decreased dose
If it reoccurs, restain until the ANC is more than 1x 109/L or the platelets are more than 50x 109/L; then restart at a reduced dose
Asymptomatic amylase or lipase elevation
Retain until the <1.5x ULN occurs
If resolved, restart at a decreased dose
If not resolved, discontinue permanently
If it reoccurs at decreased dose, discontinue permanently
Renal impairment
Mild-severe: Dose adjustment not necessary
Hepatic impairment
Mild-severe: Dose adjustment not necessary



hydroxycarbamide 

A single oral dose of 20 to 30 mg/kg/day. As an alternative, administer 80 mg/kg as a single dose every three days (for solid tumours). Concomitant irradiation treatment: 80 mg/kg as a single dosage given every three days, starting at least 1 week before radiotherapy, is considered