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. 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.
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. 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.
Risk Factors for Acute Lymphocytic Leukemia (ALL)
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.
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.
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.
Incidence of ALL is more common in Caucasians than in African Americans.
Signs and Symptoms of Acute Lymphocytic Leukemia (ALL)
Following are some common signs and symptoms of ALL:
- 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 joints
- Enlargement of the spleen and/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
Investigations for Diagnosis of Acute Lymphocytic Leukemia (ALL)
If a person is suspected to have ALL , some investigations are required to confirm the diagnosis of the disease. Further, these investigations can help in determining an appropriate treatment approach.
Following are some commonly used diagnostic tools for ALL:
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.
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 of 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.
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.
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.
Response Assessment in Acute Lymphocytic Leukemia (ALL)
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.
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.
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.
Risk Stratification of Acute Lymphocytic Leukemia (ALL)
Prognostic risk stratification refers to the classification of patients with ALL into different risk-groups based on various known/validated prognostic factors. Identified prognostic factors for ALL include Patient’s age, WBC count at the time of diagnosis, immunophenotypic or cytogenetic subtype, CNS and other organ involvement, and response to induction therapy. 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, and T-cell ALL.
T-cell ALL occurs in about 25% of the cases and is generally associated with poor disease prognosis.
Historically, patient’s age and WBC count at diagnosis have been regarded as strong independent prognostic factors for ALL. Considering the prevalence of ALL in children and adults, separate risk stratification has been proposed for the following 2 age-groups:
- Adolescent and Young Adults (AYA) patients (>/=15 to <39 years of age) and
- Adult patients (>/=40 to <60 years of age).
Young patients generally have a better disease prognosis and better response to treatment compared to the old-age individuals. The exception to this criterion is patients younger than 1 year of age who are generally considered to be at very high risk.
Presence of Philadelphia chromosome (Ph) is another important independent prognostic factor that has been known since long as a predictor of poor disease prognosis. Many clinical research studies have reported that individuals with Ph+ ALL have significantly poor disease prognosis compared those with Ph-negative ALL. Based on these findings, patients will ALL are mainly divided into the following four risk groups:
|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 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|
With the progress in understanding of the disease and advancement in genetic diagnostic techniques, immunophenotypic/cytogenetic characterization has become an important parameter risk stratification. AYA patients and adult patients (<65 years of age or without any significant comorbidities) with Ph-negative ALL can be further considered high-risk if they have any one of the following parameters:
- positive minimal residual disease (MRD),
- an elevated WBC count (>/=30* 10^9/L for B-cell ALL;
- >/=100*10^9/L for T-cell ALL),
- or presence of any of the following poor-risk cytogenetic:
- hypodiploidy (<44 chromosomes);
- BCR-ABL1-like or Ph-like ALL;
- intrachromosomal amplification of chromosome 21 (iAMP21).
Absence of all high-risk factors is considered standard risk.
Presence of the following cytogenetic abnormalities (favorable prognostic factors) has been linked to better prognosis:
- hyperdiploidy (presence of 51-65 chromosomes);
- t(12;21) chromosomal translocation (ETV6-RUNX1 subtype); and
- simultaneous trisomies of chromosomes 4, 10, and 17.
Following table summarizes various positive (favorable) and negative (unfavorable) prognostic factors for ALL and respective diagnostic tests for their determination:
|Favorable Prognostic factors||Unfavorable Prognostic factors||Diagnostic Test for Identification|
|Younger age (except less than 1 year)||Older age||NA|
|B-cell lineage||T-cell lineage||Immunophenotypic analysis or flow cytometry|
|Ph-negativity or BCR-ABL1-negativity||Ph-positivity or BCR-ABL1-positivity||fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR)|
|Normal WBC count||Elevated WBC count||Complete blood cell count (CBC)|
|simultaneous trisomies of chromosomes 4, 10, and 17||iAMP21|
|ETV6-RUNX1 subtype||BCR-ABL1–like ALL||Cytogenetic analysis or next-generation sequencing (NGS)|
|translocations in the KMT2A gene (MLL translocation)|
|mutations in the Ikaros gene (IKZF1)|
|Complex karyotype (5 or more chromosomal abnormalities)|
|CNS involvement||Lumbar puncture or Imaging technique: MRI|
|Response to induction therapy||MRD||PCR or RT-PCR|
With the availability of more data from different research studies, cytogenetics is now considered more valuable in predicting disease prognosis, while prognostic factors such as WBC count have lost its independent prognostic significance.
Treatment of Acute Lymphocytic Leukemia (ALL)
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:
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.
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.
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.
Treatment of 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.
Treatment of 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.
Treatment of 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.
Treatment of 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.
Chemotherapy for Acute Lymphocytic Leukemia
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. It may be associated with side effects like nausea/vomiting, hair loss, fatigue, cytopenias, etc due to its effect on normal body cells apart from cancerous cells.
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.
Targeted Therapy for Acute Lymphocytic Leukemia
For many years, chemotherapy has been the mainstay of treatment for ALL. However, the invention of targeted therapy has transformed the treatment of ALL, especially Ph+ ALL and other ALL subtypes with poor prognostic factors.
Targeted drugs approved for the treatment of ALL:
It is the first BCR-ABL tyrosine kinase inhibitor (TKI) approved for the treatment of Ph+ ALL both in adults (with relapsed or refractory disease) and in children (with previously untreated patients). Imatinib has been reported to be efficacious both as single-agent therapy and in combination with various chemotherapeutic regimens during initial induction, consolidation, and/or maintenance phase of Ph+ ALL treatment. The advantage of using imatinib is the substantial experience with the drug that indicates its efficacy and safety in different patient populations.
Imatinib is better tolerated in older patients and thus, indicated in combination with corticosteroids for the induction therapy of Ph-positive ALL in older adults (>65 years of age or otherwise frail). A benefit of imatinib as maintenance therapy after consolidative stem cell transplantation (SCT) in reducing the risk of relapse has also been implicated.
It is a second-generation TKI that possess 325-times more potency and a wider spectrum of activity compared to imatinib. It inhibits BCR-ABL along with src family kinases, a group of proteins that have a role in the development of resistance to imatinib therapy. Thus, dasatinib is useful in patients whose disease has not responded to (or is resistant to) imatinib.
Additionally, dasatinib is active against CNS disease owing to its better BBB penetration. Induction therapy with dasatinib in combination with corticosteroids or chemotherapy is generally recommended for patients with previously untreated or imatinib-resistant Ph+ ALL. It is also indicated as maintenance therapy for the prevention of relapse after SCT.
Nilotinib and Bosutinib
These are other second-generation TKI that possess higher potency and a wider spectrum of activity compared to imatinib. Similar to dasatinib, they are recommended in combination with corticosteroids or chemotherapy as induction therapy for patients with previously untreated or imatinib-resistant Ph+ ALL and as maintenance therapy for the prevention of relapse after SCT.
It is a third-generation TKI that is active against imatinib-resistant disease and has been approved as the subsequent treatment of Ph+ ALL resistant or intolerant to second-generation TKIs therapy, and in patients with the T315I mutation (see table below).
In patients with Ph+ ALL who have not responded to or relapsed after initial TKI-containing therapy, ABL1 kinase domain mutation analysis is generally recommended for assessing the best subsequent therapy. The following table indicates NCCN recommended best-suited TKI-based therapy for the specific mutation(s) detected in the ABL1:
|Mutation||NCCN Recommendation Treatment|
|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
Common side effects associated with TKI therapy include skin rashes, nausea, diarrhea, muscle pain, fatigue, hand and foot syndrome (swelling in hands and feet), and lower red blood cell and platelet counts.
Monoclonal Antibodies for Acute Lymphocytic Leukemia
Monoclonal antibodies are man-made antibodies which can be directed to certain proteins characteristic of cancer cells.
It is a monoclonal antibody that targets CD-20, a surface antigen present on ALL cells (especially mature B-cell ALL). It has reported to impart survival benefit in combination with the various standard multi-agent chemotherapeutic regimens in both AYA and adult patients.
It is a bispecific monoclonal antibody that simultaneously targets two proteins, CD19 protein on ALL-cells (cancer cells) and the CD3 protein on the T-lymphocytes (immune cells). Thus, this drug brings the T-cells and cancer cells close to each other and helps immune cells to destroy the cancer cells. Blinatumomab is recommended for the treatment of patients with B-cell ALL (Ph+ or Ph–) who are not responding or who have relapsed on initial treatment with chemotherapy or targeted therapy.
It is an anti-CD22 antibody that is linked to a chemotherapeutic agent (a calicheamicin derivative). This drug selectively exposes CD22 expressing ALL-cells with the chemotherapeutic drug and cause them to die. The drug has been approved for the treatment of refractory or relapsed (including >/= 2 relapse) precursor B-cell ALL (both Ph= or Ph–).
CART Cell Therapy
Tisagenlecleucel is the first-ever gene therapy approved by US FDA. Tisagenlecleucel is also known as chimeric antigen receptor (CAR) T cells therapy or simply CART therapy. Tisagenlecleucel is a customized treatment manufactured using patient’s own T-cells collected by a process known as leukapheresis (a procedure that involves separation of white blood cells from the blood and infusion of remaining blood back to the patient).
The collected T-cells are genetically modified in a laboratory using a lentivirus to have a new gene that made the cells to express CAR protein that targets CD19 expressing ALL cells. These modified T-cells identify and kill ALL-cells when infused back to the patient. It is recommended for the treatment of AYA patients (<26 years of age) with precursor B-cell ALL (both Ph+ or Ph–) and with TKI-refractory disease or >/=2 relapses.
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.