Acute Lymphocytic Leukemia (ALL)
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: Acute lymphocytic leukemia (or lymphoblastic) (ALL), Acute myeloid (or myelogenous) leukemia (AML), Chronic lymphocytic leukemia (CLL), and Chronic myeloid (or myelogenous) leukemia (CML).
Acute lymphocytic leukemia (ALL) is the most common childhood cancer in the US accounting for about 0.3% of all new cancers and about 0.2% of all cancer-related deaths. According to an estimate, in 2018, about 5960 new cases of ALL with about 1470 deaths from the disease will be observed in the US. The overall incidence of ALL has been increasing slightly during the last decade, while the mortality decreasing during the same period. ALL is more common at a young age with highest incidence observed in individuals aged below 20 years. The incidence rate of ALL is higher in Caucasians compared to African Americans and 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.
ALL is a disorder in which lymphoblasts (precursor of lymphocytes or immature lymphocytes) start dividing without control. The abnormal lymphoblasts get crowded in the red bone marrow and peripheral blood causing a reduction in the number of normal RBCs and WBCs. ALL cells can spread quickly to different organs like liver, spleen, lymph nodes, Brain, spinal cord, and testicles in males. Pathologically, ALL is defined as the presence of >/=20% lymphoblasts in the bone marrow.
The previous classification of ALL by French, American, and British (FAB) system (based on ALL cells morphology) has been largely replaced with an advanced system based on immunophenotype information derived from various cytogenetic tests. The ALL may arise from the B-cell lineage or T-cell lineage. Based on the immunophenotypes, the ALL is broadly categorized into following types: early pre-B-cell ALL, pre-B-cell ALL, mature B-cell ALL, pre T-cell ALL and T-cell ALL. Each of these types consists of different surface antigens and certain other cellular characteristics. Analysis of surface antigens and chromosomal abnormalities play important role in the diagnosis of the disease and to estimate disease prognosis. Presence of Philadelphia chromosome (Ph+), that is, a transfer of DNA between chromosomes 9 and 22, abbreviated as t(9;22) is quite common in ALL (about 25% of all cases) and this should be detected for selecting the appropriate treatment approach.
Several epidemiological studies have revealed a number of risk factors that can predispose ALL. Following is the list of such risk factors:
- Exposure to radiation: History of radiation exposure is the most potent risk factor for the development of ALL. Exposure to radiation along with chemotherapy further raises the risk.
- Industrial/Occupational exposure: Regular exposure to carcinogens like benzene and petroleum products has been indicated to increase the risk of ALL.
- Infection with certain viruses like T-cell lymphoma/leukemia virus-1 (HTLV-1) and Epstein-Barr virus (EBV) has been indicated to increase the risk of developing certain types of ALL.
- Genetic alterations: Some inherited genetic alterations have been reported to be associated with a high incidence rate of ALL, for example (e.g.), Down syndrome (generally caused by chromosomal abnormality), Fanconi anemia, Klinefelter syndrome, Ataxia-telangiectasia, Bloom syndrome, and Neurofibromatosis.
- Age and gender: ALL is more common among young age individuals and among older age individuals. Also, males are affected more compared to females.
- Ethnicity: Incidence of ALL is more common in Caucasians than in African Americans.
Signs and symptoms
Following are some common signs and symptoms of ALL, which may help in early diagnosis if attended appropriately:
- Fatigue and weakness attributable to anemia, other anemia-related symptoms may include shortness of breath and dizziness
- Recurrent infections like pneumonia due to low WBC count (leukopenia)
- Increased bleeding tendency due to low platelet count (thrombocytopenia)
- Unexplained weight loss
- Fever and night sweats
- Pain in extremities or joint in children
- Enlargement of the spleen or liver
- Enlargement of lymph nodes
- Spread of ALL cells to CNS may cause certain symptoms such as headache, seizures, vomiting, chin numbness, blurred vision, and imbalance.
If a person is suspected to have ALL due to the presented signs and symptoms, some investigations are required to confirm the diagnosis of the disease. Further, these investigations can help in determining the extent of disease or spread of the disease to different body parts, which in turn help in selecting an appropriate treatment approach. Following are some commonly used diagnostic tools for ALL:
1.Blood Tests: Blood tests provide very important information that provides direction to the diagnostic workup of ALL. Following are the commonly employed blood test for the diagnosis of the ALL:
- Complete Blood Cells Count (CBC): This test provides information on the level of RBCs, WBCs, and platelets. Usually, RBCs and platelets are reduced and WBCs may be reduced or increased.
- Blood Smear: In this test, a drop of a blood sample is spread on a glass slide and this is observed under a microscope. It helps in detecting any change in the appearance and number of various blood cells.
Apart from above blood tests, blood coagulation tests (disseminated intravascular coagulation panel) and some blood chemistry analyses (the level of creatinine, uric acid, potassium, calcium, phosphorus, and lactate dehydrogenase (LDH) level) may also be employed.
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 about the ALL cells such as the type ALL, the severity of cancerous changes involved, and the presence of specific defective genes or proteins. Following are various techniques used for collecting this information:
- Immunohistochemistry: In this technique, a very thin portion of biopsy sample is first attached to a microscope glass slide. The sample is then treated with a specific antibody which gets attached to a protein specific to certain types of cancer cells. Some reagents are then added to the treated sample that causes the bound antibody to change its color. The change in color of the antibody-protein complex can be observed under the microscope, which confirms the type of cancer cells.
- Flow cytometry: In this technique, the aspiration 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. This test can detect different types of cells along with the quantification of each type of cells.
- Cytogenetic Testing: In this technique, chromosomes are evaluated for certain defects which are common in ALL. The sample cells are first grown into the culture medium and are observed under a microscope after adding certain reagents that bind only to a specific defective portion of a chromosome. This test enables detection of chromosomal abnormalities like translocation, amplification, or deletion.
- Fluorescent in situ hybridization (FISH): In this technique, a fluorescent RNA probe is used which binds 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. Thus, this technique is preferably used for detecting chromosomal abnormalities.
- Polymerase chain reaction (PCR): This is a very sensitive diagnostic tool which can detect a very small number of leukemia cells with a specific genetic change, for example, Philadelphia chromosome. This technique is generally used to diagnose minimum residual disease (MRD) in patients after treatment.
3.Imaging Tests: Utility of imaging tests is limited for the diagnosis of ALL. However, these tests can be used to detect the involvement of different body parts by leukemia.
- Computed tomography (CT) scan: In this technique, detailed cross-sectional images of body organs are generated using x-rays. It can be utilized for scanning neck, chest, abdomen and pelvis for the diagnosis of any abnormal lymph node or involvement of liver, spleen, or other structures.
- Magnetic resonance imaging (MRI) scan: This technique provides detailed images of internal body structures using radio waves, strong magnetic field, and gadolinium-based contrast material (which is used via intravenous injection to improve the clarity of the MRI images). It can be utilized for scanning neck, chest, abdomen and pelvis for the diagnosis of any abnormal lymph node or involvement of liver, spleen, or other structures. It is considered very sensitive to detect the involvement of CNS the patients with neurological symptoms.
- Lumbar Puncture: In this procedure, a sample of cerebrospinal fluid (CSF, a biological fluid that surrounds the brain and spinal cord) is collected with the help of a needle inserted up to the space around the spinal cord through the lower part (lumbar region) of the spine. The collected sample is then analyzed in a laboratory for the presence of leukemia cells. Generally, >/=5 leukocytes cells/microliters of CSF with the presence of lymphoblasts is considered as the CNS leukemia. This technique can also be used to deliver a treatment to the CSF.
Investigational tests play an important role in assessing the response to treatment, which in turn help in selecting an appropriate second-line of treatment. Following are various terms used to indicate the different responses to treatment:
- Complete response: A complete response means absence of leukemia cells in the blood and <5% blasts in bone marrow. Any sign or symptom of the disease like spleen/liver enlargement should return to normal.
- Refractory Disease: When complete response cannot be achieved after induction treatment, the disease is termed as a refractory disease. Second-line of treatment is usually employed in such cases.
- Disease Relapse: When leukemia cells are detected in blood or any other body part (including CNS) or >5% blasts in bone marrow, after complete remission, it is known as relapsed disease.
- Minimal Residual Disease (MRD): When leukemia cells are undetectable with conventional diagnostic technique after treatment but detectable with a more sensitive technique such as PCR, or flow cytometry, it is known as MRD. Patients with MRD after treatment are more likely to have disease relapse. Thus, after induction treatment, MRD assessment should be performed to assess the disease prognosis.
The severity of ALL is generally estimated based on various prognostic factors such as Patient’s age, WBC count, chromosomal mutations, CNS involvement, and response to induction therapy, along with other factors. With the progress in understanding about the disease and genetic abnormalities involved, immunophenotypic/cytogenetic characterization has become an important parameter for selecting an appropriate treatment approach. Presence of Philadelphia chromosome predicts a poor disease outlook. Patient’s age and performance status is another most important parameter for the selection of appropriate treatment. Based on the age at ALL diagnosis, the patient population is generally divided into 2 groups: adolescent and young adults (AYA) patients and Adult patients. Young patients generally have a better outcome. The following table describes major ALL risk groups and associated characteristics
|Ph+ ALL in AYA patients||Patients with age 15 to 39 years and are positive for Philadelphia chromosomal abnormality|
|Ph+ ALL in Adult patients||Patients with age >/=40 years and who are positive for Philadelphia chromosomal abnormality|
|Ph- ALL in AYA patients||Patients with age 15 to 39 years and are negative for Philadelphia chromosomal abnormality|
|Ph- ALL in Adult patients||Patients with age >/=40 years and who are positive for Philadelphia chromosomal abnormality|
The treatment of ALL depends on many factors including but not limited to the type of disease, patient’s age, chromosomal mutations, CNS involvement, performance status of the patient, along with other factors. ALL treatment generally takes long (about 2 to 3 years) and mainly include the following phases:
1.Induction: The main aim of induction therapy is to achieve remission, that is, depletion of leukemia cells from the blood and bone marrow. However, this does not mean a cure as some leukemia cells may still exist that are undetectable by conventional diagnostic techniques. Thus, further treatment is usually recommended. Induction treatment usually includes multiagent chemotherapy and corticosteroid with or without a targeted agent.
The treatment for ALL usually includes CNS prophylaxis since the leukemia cells quickly spread to CNS. Thus, even when leukemia cells are not diagnosed in the CSF, treatment with radiotherapy, intrathecal chemotherapy (directly injected into the CSF), or high dose intravenous chemotherapy is given to all patients starting from induction and throughout the treatment.
2.Consolidation: The main aim of consolidation treatment is to wipe out any remaining leukemia cells from the body after induction treatment. Allogenic or autologous stem cell transplant (SCT) may be considered in patients with poor-prognostic factors who are good candidates for the same. CNS prophylaxis continues during this phase.
3.Maintenance: The main aim of maintenance treatment is to avoid disease recurrence after induction and consolidation therapy. The maintenance treatment regimen usually includes mild chemotherapy (especially anti-metabolites) with or without corticosteroid and targeted agent depending upon the type of ALL. The duration of maintenance therapy is generally about 1 to 2 years.
Based on the results obtained from various clinical research studies carried out so far, following are the preferred treatment approaches for different types of diseases and different patient populations:
|Risk Group||Preferred Treatment|
|Ph+ ALL in AYA patients
(age 15 to 39 years)
|The preferred induction treatment regimen includes multiagent chemotherapy with corticosteroid with a TKI. Allogenic SCT may be employed if a matched donor is available OR multiagent chemotherapy with a TKI should be employed during consolidation. Maintenance therapy for about 1-2 years with a TKI with or without chemotherapy is considered after consolidation. Periodic MRD assessment and CNS prophylaxis is recommended.|
|Ph+ ALL in Adult patients
(age >/=40 years)
|For patients with age less than 65 years and who are otherwise healthy (without any accompanying comorbidities), the preferred treatment approach is similar to that for AYA patients.
For patients with age more than 65 years OR who are not overall healthy (have accompanying comorbidities), the preferred induction treatment regimen includes low-intensity chemotherapy combined with a TKI. Chemotherapy (low-intensity) along with a TKI can be employed during consolidation. Maintenance therapy for about 1-2 years involving a TKI with or without chemotherapy is considered after consolidation. Periodic MRD assessment and CNS prophylaxis is recommended.
|Ph- ALL in AYA patients
(age 15 to 39 years)
|The preferred induction treatment regimen includes multiagent chemotherapy with corticosteroid. Allogenic SCT may be employed if a matched donor is available OR multiagent chemotherapy should be employed during consolidation. Maintenance therapy for about 1-2 years is considered after consolidation. Periodic MRD assessment and CNS prophylaxis is recommended.|
|Ph- ALL in Adult patients
(age >/=40 years)
|For patients with age less than 65 years and who are otherwise healthy (without any accompanying health problem), the preferred treatment approach is similar to that for AYA patients.
For patients with age more than 65 years OR who are not overall healthy (have accompanying comorbidities), the preferred induction treatment regimen includes low-intensity chemotherapy. Chemotherapy (low-intensity) can be employed during consolidation. Maintenance therapy for about 1-2 years is considered after consolidation. Periodic MRD assessment and CNS prophylaxis is recommended.
Following is the brief description of various treatment types employed for ALL:
1.Chemotherapy: Chemotherapy means treatment with anti-cancer drugs that kill or decrease the growth of rapidly-growing cancer cells. Chemotherapy may be employed in combination with targeted drugs for the management of ALL having certain genetic abnormalities for which targeted drugs are available. It may also be combined with corticosteroids to accelerate the benefit achievement. Chemotherapy may also be injected directly in the CSF for CNS prophylaxis/treatment. Many pharmaceutical companies are conducting a number of clinical trials to find out new drugs and drug-combinations with increased efficacy and specificity to target ALL cells. Chemotherapy may be associated with side effects due to its effect on normal body cells apart from cancerous cells.
2.Corticosteroids: These are a category of drugs which are structurally similar to cortisone, a hormone produced by the adrenal cortex. Examples of corticosteroids include dexamethasone and prednisone that are generally employed in the treatment regimen for ALL. These drugs may have their own side effects like hyperglycemia, weight gain, mood changes, weakness in bones, etc.
3.Targeted Therapy: Targeted drugs are designed to target a specific gene or protein characteristic of the ALL cells. Examples of targeted drugs for ALL include TKIs (like imatinib, dasatininb, nilotinib, bosutininb, and ponatinib) that target Philadelphia chromosomal abnormality. These drugs can be used in combination with other therapeutic agents or alone for the treatment of Ph+ ALL.
4.Monoclonal Antibodies: Monoclonal antibodies are man-made antibodies which can be directed to certain proteins characteristic of cancer cells. For the treatment of ALL, Blinatumomab is one such molecule, which gets attached to the CD19 protein on ALL cells and the CD3 protein on the T-lymphocytes. This brings the T-cells close to the cancer cells, and thus, helps immune cells to destroy the cancer cells. It is generally employed for the treatment of ALL that is not responding to chemotherapy or targeted agents.
5.Radiation Therapy: Radiation therapy (or radiotherapy) uses high-energy x-rays or other high-energy radiations which are directed to the affected area to kill cancerous cells. For ALL, an external beam radiation therapy is generally employed for prophylaxis or treatment for CNS leukemia. Radiotherapy may be employed with high dose chemotherapy before SCT.
6.Stem Cell Transplant (SCT): SCT is the standard of care in patients with poor risk ALL. It is generally employed for the treatment of ALL in patients who are good candidates for it (younger patients in good health). Following are major types of stem cell transplant techniques:
- Autologous SCT: In this technique, the patient’s own stem cells are first collected from the bone marrow tissue or peripheral blood (preferred nowadays). Then, the patient receives high-dose chemotherapy with or without radiation therapy to kill the leukemia The collected stem cells are re-administered to the patient which slowly replenish the blood cells in the patient’s body.
- 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 HLA closely matches with that of the patient.
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 ultimate goals of treating stomach cancer:
- Prolongation of life
- Reduction of symptoms
- Improvement in quality of life
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