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Chronic Myeloid Leukemia: Risk Factors, Symptoms, Staging, Treatment

OVERVIEW

Leukemia is the tenth most common cancer constituting about 3.5% of all cancers in the United States (US).

Leukemia is divided into four main types:

  1. Acute lymphocytic (or lymphoblastic) leukemia (ALL),
  2. Acute myeloid (or myelogenous) leukemia (AML),
  3. Chronic lymphocytic leukemia (CLL), and
  4. Chronic myeloid leukemia (or myelogenous)(CML).

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.

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RISK FACTORS

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.
  • Age: CML is more common among old age individuals and its risk increase with the increase in age.
  • Gender: CML is more common in males than females.

SIGNS AND SYMPTOMS

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

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:

  1. Blood Tests: 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.
  2. 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.

    Cytogenetics – 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).

    Flow cytometry: 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).


    Apart from establishing the diagnosis of CML, investigational tests play an important role in assessing the response to treatment. Following are various terms used to indicate the different responses to treatment:
  • 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 CHRONIC MYELOID LEUKEMIA AND RISK STRATIFICATION


Based on the clinical manifestations, CML can occur in following three phases:

  1. Chronic Phase: 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.
  2. Accelerated Phase: 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).
  3. Blast Phase: 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.

Following 2 systems are used to stratify the patients with CML in different risk groups:

  • Sokal system: 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.

  • Hasford system: 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.

CHRONIC MYELOIOD LEUKEMIA TREATMENT

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.

Following are the preferred treatment approaches for different phases of CML, but the final decision is taken after clinical assessment of the patient by an oncologist.

PHASE OF CML TREATMENT
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.

Following is a brief description of various treatment types employed for CML:

  1. Targeted Therapy: Targeted drugs are designed to target a specific gene or protein characteristic of the CML cells. Examples of targeted drugs for CML include imatinib (first generation), Dasatinib, Nilotinib, Bosutinib, and Ponatinib (second generation) that target tyrosine kinase (a protein made by BCR-ABL fusion gene, characteristic of CML cells).

    These drugs have revolutionized the treatment for CML. These drugs are generally used for chronic phase CML and accelerated phase CML. The TKIs are usually associated with several side effects and selection of appropriate TKI is generally based on the side-effects associated with the agent.

  2. 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.

  3. Chemotherapy: 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.

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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