Chronic myeloid leukemia (CML) accounts for about 1.5% of all leukemia cases, about 0.5% of all new cancers, and about 0.2% of all cancer-related deaths in the US. The overall incidence rate of CML has been slightly increasing while the mortality rate of CML has been declining during the last decade.
CML more commonly affects older age individuals with highest incidences observed in individuals aged between 65 to 74 years. The incidence rate of CML is slightly higher in males than in females.
The blood is a connective tissue consisting of a liquid extracellular matrix (the plasma) and suspended formed elements (comprising blood cells and cell fragments). The 3 main components of formed elements include red blood cells (RBCs), white blood cells (WBCs) and platelets.
The WBCs are further divided into various subtypes based on their appearance under the microscope (with the application of different staining): neutrophils, basophils, eosinophils, monocytes, and lymphocytes (T-cells, B-cells, and natural killer cells). Each type of blood cell has a distinct function and is produced from pluripotent stem cell in the red bone marrow by a process called hemopoiesis.
CML is a disorder in which myeloid blasts (precursor of myeloid cells) start dividing without control. This is postulated to be caused by a genetic change (reported in more than 95% of all CML patients) in the immature myeloid cells, which is referred to as Philadelphia chromosome (Ph) – a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene.
The fusion gene gives rise to a protein with deregulated tyrosine kinase activity that turns the cells to CML cells (the abnormal myeloid precursors with Ph+), which divide indefinitely and get crowded in the red bone marrow and peripheral blood causing a reduction in the number of normal blood cells. Characteristically, CML is a slow-growing disorder which is mostly diagnosed in chronic phase, which may become aggressive (progressed to accelerated or blast phase) if not treated appropriately.
Risk Factors of CML
Not many risk factors have been identified for CML. Following is the list of such risk factors:
Exposure to Radiation
History of radiation exposure is one of the most important risk factors for the development of CML. Some individuals who had been exposed to high level of radiations like the survivors of an atomic bomb blast or nuclear reactor accident and patients who had radiation treatment are considered to be at increased risk of developing CML.
CML is more common among old age individuals and its risk increase with the inrease in age.
CML is more common in males than females.
Signs and Symptoms of CML
Following are some common signs and symptoms of CML:
- Unexplained weight loss
- Loss of appetite
- Abdominal discomfort or mass (Enlargement of the liver or spleen)
- Fever and night sweats
- Fatigue and weakness attributable to anemia, other anemia-related symptoms may include shortness of breath and dizziness
- Recurrent infections like pneumonia due to a shortage of normal WBC count (leukopenia). However, the overall WBC count may be high due to the presence of abnormal cells.
- Increased bleeding tendency, bruising, frequent or severe nosebleeds, and bleeding gums due to low platelet count (thrombocytopenia). However, some patients may have too many platelets (thrombocytosis), but these are not normal-functioning platelets.
- Pain in the bones or joints
Investigations for CML
If a person is suspected to have CML, some investigations are required to confirm the diagnosis of the disease. Further, these investigations can help in determining the phase of CML, organ involvement, cytogenetic abnormalities, etc. which in turn help in selecting an appropriate treatment approach.
Following are some commonly used diagnostic tools for CML:
Blood tests provide very important information that provides direction to the diagnostic workup of CML. Following are the commonly employed blood test for the diagnosis of the CML:
Complete Blood Cells Count (CBC): This test provides information on the level of RBCs, WBCs, and platelets. In most cases of CML, high level of WBCs and low RBC s and platelets are observed. In some cases, very high level of platelets may also be observed.
Blood Smear: In this test, a drop of a blood sample is spread on a glass slide and this is observed under a microscope. This test helps in detecting any change in the appearance of various blood cells. Appearance and relative percentage of myeloid precursors can be estimated by this test, which in turn help in establishing the diagnosis of CML.
Bone Marrow Aspiration/Biopsy
Aspiration samples contain a small number of cells and biopsy contains a tiny piece of tissue collected from the bone with the help of a biopsy needle. The biopsy sample is then tested in a laboratory and can provide very useful information like phase of CML (chronic, accelerated or blast), cytogenetic abnormalities, etc. Following are various techniques used for collecting this information:
Fluorescent in situ hybridization (FISH)
In this technique, fluorescent RNA probes are used, which bind to a specific portion of a chromosome in the sample cells. Then, the sample can be examined under a microscope to determine the presence of certain chromosomal abnormalities like translocation, addition, or deletion.
This technique is very sensitive, fast, and accurate. It is preferably used for detecting Philadelphia chromosome (Ph), the most common genetic abnormalities in the CML cells.
This test can help in detecting Philadelphia chromosome along with additional chromosomal abnormalities like trisomy 8, isochromosome 17q, second Ph, and trisomy 19. Presence of additional cytogenetic abnormalities is generally associated with poor disease prognosis.
Reverse-transcriptase polymerase chain reaction (RT-PCR)
This is the most sensitive diagnostic tool available today, which can detect a very small number of CML cells with a specific genetic change (BCR-ABL1 gene) in blood or bone marrow sample. This technique can be used either as a qualitative tool to establish the diagnosis of CML or as a quantitative tool after to assess the number of BCR-ABL1 transcripts, and thus, the efficacy of treatment or the minimum residual disease (MRD).
In this technique, the biopsy sample is first treated with some fluorescent antibodies that get attached to certain specific proteins (antigens) on the surface of cells. The treated sample is then analyzed using a laser beam and a detector attached to a computer. It is useful in blast phase of CML to detect the lineage (myeloid or lymphoid).
Response Assessment in CML
Complete hematologic response (CHR)
A CHR means complete normalization of peripheral blood counts with leukocyte count <10 x 10^9/L; platelet count <450 x 10^9/L; no immature cells, such as myelocytes, promyelocytes, or blasts in peripheral blood; and no signs and symptoms of disease with the disappearance of palpable splenomegaly.
Complete Cytogenetic Response (CCyR)
A CCyR means an absence of Ph+ cells in the bone marrow.
Partial cytogenetic response (PCyR)
A PCyR means a presence of 1% to 35% of Ph+ cells in the bone marrow.
Major cytogenetic response (MCyR)
An MCyR (includes both complete and partial responses) means a presence of 0 to 35% of Ph+ cells in the bone marrow.
Minor cytogenetic response
A minor cytogenetic response means a presence of >35% of Ph+ cells in the bone marrow.
Complete molecular response (CMR)
A CMR means an absence of BCR-ABL1 gene in the bone marrow when assessed using RT-PCR.
Major molecular response (MMR)
An MMR means a presence of BCR-ABL1 </=0.1% by RT-PCR or >/=3-log reduction in BCR-ABL1 mRNA from the standardized baseline if RT-PCR is not available.
Early molecular response (EMR)
An EMR means a presence of BCR-ABL1 </=10% of the baseline at 3 and 6 months.
Phases of CML
Based on the clinical manifestations, CML can occur in following three phases:
Chronic phase CML is characterized by the presence of less than 10% blast cells in the peripheral blood and bone marrow. The patients with chronic phase CML usually have no or mild symptoms and respond well to standard treatment.
According to WHO criterion, the accelerated phase CML is defined as the presence of 10-19% blast cells in blood or bone marrow, >/=20% basophils in the peripheral blood or bone marrow, persistent thrombocytopenia (platelet count <100 x 10^9/L) unrelated to therapy or persistent thrombocytosis (platelet count >1000 x 10^9/L) unresponsive to therapy, increasing WBCs and spleen size, or clonal cytogenetic evolution in Ph+ cells (trisomy 8, isochromosome 17q, second Ph, and trisomy 19).
According to the WHO criteria, the blast phase CML is defined as the presence of >/=20% blast cells in the peripheral blood or bone marrow, extramedullary blast proliferation, or large foci or clusters of blasts in bone marrow biopsy.
Scoring Systems for CML Risk Stratification
The Sokal score is calculated based on the patient’s age, spleen size, platelet count, and percentage of blasts in the peripheral blood. CML patients are assigned a risk group (Low, Intermediate, or High) based on the Sokal score (<0.8, 0.8-1.2, and >1.2), respectively.
The Hasford system includes 2 additional prognostic factors to those included in the Sokal system, that is, level of basophils and eosinophils in the blood. CML patients are assigned a risk group (Low, Intermediate, or High) based on the Hasford score (</=780, 781-1480, and >1480), respectively.
Treatment of CML
The treatment of CML depends on many factors, including but not limited to, the phase of the disease, risk group, associated comorbidities (to choose the drugs which do not have similar side effects), and performance status of the patient.
Chronic Phase (CP) CML
In low-risk patients, both first-generation and second-generation tyrosine kinase inhibitors (TKIs) are considered as the standard treatment; however, in case of intermediate to high-risk patients, second-generation TKIs are considered the preferred treatment.
After starting the treatment, RT-PCR is done at regular intervals to assess the response to treatment. Further decision whether to continue the same drug or change the treatment is taken depending on the response.
Accelerated Phase (AP) CML
In patients with newly diagnosed accelerated phase CML, TKI therapy is considered the preferred treatment.
In case of patients with chronic phase CML who have progressed to accelerated phase, mutational analysis is done to check for resistance. Thereafter, a different TKI is used that is active against the mutation detected. Allogeneic SCT can be considered in case of mutations resistant to TKIs.
Blast Phase (BP) CML
In patients with newly diagnosed blast phase CML, induction treatment for ALL or AML is given, depending upon whether it’s lymphoid or myeloid blast crisis, respectively. Allogeneic SCT is indicated once patient has attained CR after induction. TKI is given throughout along with chemotherapy and continued thereafter.
In case of patients whose disease has progressed from CP or AP to blast phase, induction treatment for ALL or AML is given, depending upon whether it’s lymphoid or myeloid blast crisis, respectively. Allogeneic SCT is indicated once patient has attained CR after induction. Mutational analysis is done to check for resistance. Thereafter, a different TKI is used that is active against the mutation detected. TKI is given throughout along with chemotherapy and continued thereafter.
Brief description of various treatment modalities employed for CML
Targeted drugs are designed to target a specific gene or protein characteristic of the CML cells. Most patients (>95%) with CML have a well-characterized genetic abnormality – Philadelphia (Ph) chromosome that gives rise to the BCR-ABL-1 fusion gene. The defective fusion gene encodes for a protein that has intrinsic tyrosine kinase activity responsible for the uncontrolled proliferation of the CML cells.
Following is the list of various TKIs currently approved for the treatment of patients with CML:
It is the only first-generation tyrosine kinase inhibitor (TKI) that inhibits the abnormal activity of BCR-ABL1. It is the first targeted drug approved for the treatment of CML in first-line setting due to significantly improved clinical outcome and overall survival (OS) observed in clinical studies. Side effects of imatinib include nausea, diarrhea, muscle pain, fatigue, skin rash, and fluid build-up in different body parts.
It is a second-generation TKI that has about 350 times more potency than imatinib for inhibition of BCR-ABL tyrosine kinase. It was found effective in some patients who were resistant to imatinib treatment. It has also been approved for the treatment of patients with CML in first-line settings owing to better response and fewer chances of disease progression observed in large clinical studies. Side effects of dasatinib include edema, low blood cell counts, nausea, diarrhea, and skin rashes.
It is another second-generation TKI that is a structural analog of imatinib but is about 50 times more potent than imatinib. Similar to dasatinib, nilotinib may be effective against some cases that are resistant to imatinib. Also, compared to imatinib, it showed a better response to treatment and fewer chances of disease progression when employed in the first-line setting. It has also been approved for the first- and second-line treatment of CML patients.
It is another second-generation TKI that is a potent inhibitor of BCR-ABL1 kinase activity. Although it was initially approved to be used in the second-line setting, it has recently been approved to be used in the first-line settings for the treatment of patients with CML. Side effects include nausea, vomiting, diarrhea, abdominal pain, fever, fatigue, low blood cell counts, and liver damage.
It is the third-generation TKI that is a potent inhibitor of BCR-ABL and is the only TKI active against the T315I mutation. It is approved for the treatment of patients who are not responding to prior therapy or have T315I mutation. Side effects of the drug include abdominal pain, headache, skin problems, fatigue, high blood pressure, and other heart-related problems.
Based on the results obtained from various clinical research studies following inferences have been drawn:
First-generation TKI–Imatinib, and second-generation TKIs–bosutinib, dasatinib, and nilotinib are generally employed for the treatment of most of CML patients due to their proven effective in patients with newly diagnosed chronic phase (CP)-CML. The second generation TKIs are preferred over imatinib in patients with high-risk disease, and in women who want to achieve quick response for fertility-related reasons. Of note, the overall survival rate with second-generation TKI remain comparable to imatinib.
The selection of the most appropriate TKI drug (among the second-generation agents) also depends upon the side-effects associated with the drug.
Selection of Second-line Treatment for CML
The response to first-line treatment with TKIs is one of the key prognostic indicators of the clinical outcome in CML patients. The response to treatment is usually assessed by assessing the level of BCR-ABL1 transcript in the blood or bone marrow with the help of reverse transcriptase- polymerase chain reaction (RT-PCR) technique.
The requirement for continuation of the same treatment regimen or a change in treatment regimen is then assessed based on the level of BCR-ABL1 achieved at different time points as shown in the table below:
|Time of Response Assessment||BCR-ABL1 Level||Clinical Consideration|
|3 months||</=10%||Disease is sensitive to the current treatment regimen and there is no need to change the current treatment regimen.|
|>10%||There are chances of resistance development on the current treatment regimen. Assessment of compliance to treatment and mutational analysis is recommended for these patients.|
|6 months||</=10%||Disease is sensitive to the current treatment regimen and there is no need to change the current treatment regimen.|
|>10%||Disease is resistant to the current treatment regimen. Second-line treatment regimen should be selected based on results from mutational analysis and considering other factors.|
|12 months||</=1%||Disease is sensitive to the current treatment regimen and there is no need to change the current treatment regimen.|
|>1% but </=10%||There are chances of resistance development on the current treatment regimen. Assessment of compliance to treatment and mutational analysis is recommended for these patients.|
|>10%||Disease is resistant to the current treatment regimen. Second-line treatment regimen should be selected based on results from mutational analysis and considering other factors.|
|15 months or more||</=1%|
|>1%||Disease is resistant to the current treatment regimen. Second-line treatment regimen should be selected based on results from mutational analysis and considering other factors.|
Mutational Analysis in CML
CML patients who do not achieve a predefined response to the first-line TKI therapy or who progressed on the initial TKI-therapy are recommended to undergo a mutation analysis. This is performed by next-generation sequencing method or conventional sequencing method.
The mutational analysis help in detection of specific mutation(s) that may have played a role in the resistance development to the initial TKI used. In case a mutation is detected, appropriate second-line therapy with an alternate TKI agent can be started based on the detected mutation. Following table indicate the most appropriate second-line TKI agents for different mutations detected in the mutational analysis.
|Y253H, E255K/V, or F359V/C/I||Dasatinib|
|F317L/V/I/C, T315A, or V299L||Nilotinib|
|E255K/V, F317L/V/I/C, F359V/C/I, T315A, or Y253H||Bosutinib|
In case of the absence of any mutation, a second line treatment therapy is selected based on the overall health of the patient and risk score. Second generation TKIs are generally preferred over imatinib for second-line treatment due to the lower risk of disease progression, especially in patients with an intermediate- to high-risk score.
Ponatinib, a third-generation TKI, is the only active TKI against the T315I mutation. It is recommended for patients with T315I mutation. Omacetaxine, a chemotherapeutic agent, can also be employed for the treatment of patients with the T315I mutation and for patients who have progressed on 2 or more prior TKIs.
Stem Cell Transplant (SCT)
SCT can be considered for the preferred treatment of CML in some selected patients who are good candidates for the same (good performance status) and are not responding to TKIs therapy, or patients in blast phase post induction treatment.
Allogenic stem cell transplant is mainly used for CML.
Allogeneic SCT: In this technique, healthy stem cells to be administered to the patient after high dose chemotherapy are obtained from another person known as the donor. It is very important that donor is a close blood relative (preferably a sibling) so that donor’s HLA type closely match with the patient’s.
The allogenic SCT is more beneficial than autologous SCT because donor’s stem cells help in removing any remaining leukemia cells (due to graft versus leukemia effect). Thus, allogeneic SCT is mostly used for the treatment of CML. However, allogeneic SCT is riskier due to the graft-versus-host disease in which the new immune cells originated from donor’s cells attack the host cells.
Chemotherapy means treatment with anti-cancer drugs that kill or decrease the growth of rapidly-growing cancer cells. After the invention of the TKIs, chemotherapy is not preferred to be employed for the treatment of CML. However, chemotherapy may be employed in combination with TKIs for the management of blastic phase CML.
This may help in improving the overall quality of life by providing relief from the symptoms caused by the CML. These include but are not limited to using drugs to reduce pain and other symptoms such as vomiting, fatigue or external-beam radiation therapy for bleeding or pain, etc.
It is very important to assess the benefits of each treatment option versus the possible risks and side effects before making a treatment decision. Sometimes patient’s choice and health condition are also important to make a treatment choice.
Following are the goals of treating CML:
- Prolongation of life
- Reduction of symptoms
- Improvement in quality of life
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