Acute Lymphoblastic Leukemia Cancer
Acute Lymphoblastic Leukemia Cancer
Leukemia is a type of cancer that originates in cells that would normally mature to form different types of blood cells. Depending on the pace of growth leukemia can be categorized into – acute leukemia or chronic leukemia.
If cancerous cells build up in the blasts cells rapidly filling the marrow and interfering with normal functions then it is called as acute leukemia. Acute leukemia is a fast-growing cancer that usually gets worse quickly and it demands fast and aggressive treatment.
Chronic leukemia occurs in more mature lymphoid or myeloid cells. The irregular cells build up in the bone marrows over a period of years, interrupting the production of normal blood cells and spreading to other parts of the body.
Acute Lymphoblastic Leukemia
Also called acute lymphocytic leukemia or acute lymphoid leukemia, ALL is a condition in which the bone marrow makes too many immature lymphocytes. It is a cancer of the bone marrow and young white blood cells which if not treated on time, can progress rapidly.
Bone marrow constitutes the soft inner part of some specific bones such as the bones in the skull, shoulder blades, ribs, pelvic bones, and backbones.
In the bone marrow, blood stem cells develop to become mature blood cells. A blood stem cell may either become a myeloid stem cell or it may turn out to be a lymphoid stem cell.
The myeloid stem cell may produce any of the three blood cells viz.–
- Red Blood Cell that carries Oxygen,
- White Blood Cells that fights infection
- Platelets play a crucial part in clotting of blood to stop bleeding.
A lymphoid stem cell becomes a lymphoblast cell which may then become one of three types of lymphocytes (white blood cells), viz.
- B lymphocytes make antibodies to help fight infection,
- T lymphocytes assist the B lymphocytes in making the antibodies.
- Natural killer cells that attack cancer cells and viruses.
What happens in Acute Lymphoblastic Leukemia?
Acute lymphoblastic leukemia is a malignant disease of the bone marrow in which immature lymphoblasts or lymphocytes proliferate rapidly replacing the healthy cells of the marrow.
In Acute Lymphoblastic Leukemia, too many stem cells become lymphoblasts thus producing excess of B lymphocytes or T lymphocytes. These leukemic cells are immature and are not apt in their functionalities, i.e. they fail to make antibodies and fight infections. As the number of leukemic cells increase in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets, which may lead to infection, anemia, and easy bleeding.
These leukaemia cells gradually invade the blood and can further spill throughout the body to distant organs, like liver, spleen, central nervous system, testicles or the lymph nodes. Usually, ALL does not produce tumors. It’s the percentage of immature cells in the marrow which is used to classify the stages.
Types of ALL
Acute lymphoblastic leukemia is sub-typed into two broad categories –
- B-cell ALL
- T-cell ALL.
They are further categorized as:
- Acute B-lymphoblastic leukemia: B-cell ALL makes one prone to infections, as the B lymphocytes are responsible for immunity of the body.
- Acute precursor B-cell leukemia: It is a form of ALL in which a large number of B-cell lymphoblasts are crowded in the blood and bone marrow.
- Philadelphia-positive ALL (Ph+ ALL): It occurs due to a mutation in genetic code that fuses two genes together. This BCR-ABL gene, also known as the Philadelphia Chromosome, can cause the white blood cells to become cancerous.
- Acute T-lymphoblastic leukemia: It affects the lymphoid-cell-producing stem cells, a type of white blood cell called T lymphocytes
- Natural killer (NK) cell leukemia: It is a rare neoplasm of mature natural killer cells, with an extremely poor survival rate.
According to World Health Organisation (WHO) system, ALL is sub-typed based on the type of lymphocyte (white blood cell). This aids in planning the treatment and predicting the prognosis. There are three different subtypes:
- Pre (precursor) B cell ALL: This is the most common type of ALL found in adults.
- Mature B cell ALL: Also called Burkitt type ALL, this occurs due to particular genetic changes.
- Pre (precursor) T cell ALL: This is more likely to affect young adults and men.
Occurrence Rate of ALL:
Acute lymphoblastic leukemia is the most common pediatric malignancy accounting for 25% of overall childhood cancer and 75% of leukemia cancers. Though ALL can occur at any age, they are mostly found in children under the age of 15 or in adults over the age of 45. The risk of developing ALL is highest in children below the age of 5. The risk then declines in the mid-20s, and raises again after the age of 50.
In India, leukemia is the most common childhood cancer with relative proportion varying between 25 - 40%. Out of this, 60 - 85% of cases reported falls under acute lymphoblastic leukemia type.
The worldwide incidence rate of ALL is reported to be ~ 1 – 4.75/100,000 individuals with a male : female prevalence of roughly 1•3:1. In spite of significant progress made in the treatment of ALL, the adult survival rate is poorer (35% long term survival) against an overall survival of 80% at 5 years. (Bassan and Hoelzer 2011)
Most of the symptoms of acute lymphoblastic leukemia are caused due to the shortage of healthy blood cells. Acute Lymphoblastic Leukemia can cause a variety of symptoms depending on the type of cells and the spread of the disease:
- Frequent infections or fever: As the number of healthy white blood cells declines the body’s immunity system starts breaking down. This results in regular invasion by pathogens causing frequent sickness.
- Anaemia: It is a condition referring to a lower number of red blood cells which causes weakness, fatigue and shortness of breath. Symptoms of anaemia, such as pallor, fatigue, dizziness, palpitations, etc are also reported in some cases.
- Bruising or bleeding easily: Inadequate number of red blood cells and platelets causes easy bleeding and bruising. Most often bleeding of gums while brushing can be witnessed.
- Thrombocytopenia: Thrombocytopenia is a condition characterized by abnormally low levels of thrombocytes (platelets) in the blood. The low level of thrombocytes prevents clotting which results in heavy bleeding.
- Neutropenia: It is a condition caused by low number of white cells and the immune system fails to protect the body against infection due to a lack of neutrophils (a type of white cell).
- Pancytopenia: Low numbers of all three blood cell viz. red blood cells, white blood cells, and platelets is called pancytopenia.
- Swelling and pain in joints: Too many abnormal white blood cells accumulating in the bones, joints or lymph glands may cause pain and swelling.
- Breathlessness and dizziness: Lack of red blood cells may cause breathlessness.
- Weakness, fatigue and unaccounted weight loss: Low count of red blood cells result in fatigue, weakness of the body and unaccounted weight loss.
- Feeling cold: Blood cells play an important role in maintaining body’s temperature. Low functional blood cells result in coldness.
- Skin Problems: The patient may suffer from pale skin and rashes from skin infiltration with leukemic cells. Black-and-blue marks (bruises) may appear on the skin without any apparent reason. Pinhead-size red spots under the skin (called petechiae) could also be spotted in some cases.
Signs of childhood ALL:
ALL is more common among children below the age of 5. The following signs and symptoms may suggest possibility of childhood ALL and visiting a doctor for an early diagnosis or to rule out the possibility is indicated.
- Loss of appetite.
- Easy bruising or bleeding.
- Petechiae (flat, pinpoint, dark-red spots under the skin caused by bleeding).
- Bone or joint pain
- Painless lumps in the neck, underarm, stomach, or groin.
- Pain or feeling of fullness below the ribs.
- Weakness, fatigue, or pale look.
Other potential signs and symptoms of ALL may include:
- Night sweats
- Aches in the arms, legs or hips
- small dark red spots on your skin
- Heavy periods or blood in urine
Depending upon the location of the leukemia cells other symptoms may include:
- Swollen belly from leukemia cells in the liver or spleen
- Enlarged lymph nodes such as in the neck or groin, underarms, or above the collarbone
- Headache, vomiting, seizures, or poor eyesight problems are also reported in cases where the cancer cells have spread to the brain
Though experiencing one or more of these symptoms do not ascertain that one is suffering from acute lymphoblastic leukemia, yet visiting a doctor and getting the tests done would elucidate the root cause of these symptoms thus leading to proper diagnosis, treatment and better outcome.
The exact causes of Acute Lymphoblastic Leukemia are still under scrutinization; however, ALL is typically associated with having more B lymphatic cells than T cells. B cells help prevent germs from infecting the body while T cells destroy the infected cells. B cells respond to pathogens by producing large quantities of antibodies which neutralize invading microorganisms like bacteria and viruses. In response to pathogens some T cells, called T helper cells, produce cytokines that direct the immune response, while other T cells, called cytotoxic T cells, produce toxic granules that contain powerful enzymes which induce the death of pathogen-infected cells.
ALL results from a genetic mutation to the DNA of a developing stem cell in the bone marrow. The damaged cell becomes a leukemic cell and multiplies uncontrollably into billions of cells called leukemic lymphoblasts. The leukemic lymphoblasts grow rapidly but fail to function normally and block the production of normal cells.
What are the risk factors for Acute Lymphoblastic Leukemia?
There are a few known risk factors associated with Acute Lymphoblastic Leukemia that may increase the chances of getting this disease. But it is not yet known whether these risk factors are actual causes of the disease. Risk factors associated with the disease include:
- Radiation exposure: Exposure to very high doses of radiation either accidentally (nuclear accident) or therapeutically (to treat other cancers).
- Chemical Exposure: Exposure to chemicals like benzene, smoking and other tobacco use, or certain types of drugs used to treat other types of cancer, exposure to certain cleaning products, detergents, and paints that contain ammonia or carcinogenic ingredients may increase the risk of developing ALL.
- Gender: Males are more prone to ALL than females.
- Genetic disorders: Although ALL does not appear to be an inherited disease, some genetic disorders, such as Down syndrome, neurofibromatosis, Klinefelter syndrome, Fanconi anemia, Schwachman syndrome, Bloom syndrome and ataxia telangiectasia are considered to be ALL risk factors.
- Family history: Children with parents diagnosed with leukemia were reported to have a similar risk of ALL as that of general population. A higher risk of ALL is observed among children with affected siblings.
Since there are no known controllable risk factors except exposure to radiation and chemicals. Hence, there is no known way to prevent the naturally occurring cases of ALL.
The general approach to stage cancer is by using a standardized numbered staging system. The stage of a cancer describes the size of the tumor, spread of the disease and its relative possibility of getting cured. Staging is essential for determining the optimal treatment option.
However, in case of Acute Lymphoblastic Leukemia, this conventional method of staging does not work, as the disease originates within the bone marrow and spreads rapidly to other organs usually without the trace of any tumor. So, staging of ALL is mainly determined by the considering the subtype of ALL, percentage of leukemic cells in the bone marrow and the age of the patient.
Staging of ALL usually involves several tests to identify the subtype of ALL. Some of the approved staging systems are described below:
ALL classification based on immunophenotype
Immunophenotyping is a way to classify ALL based on the type of lymphocyte (T cell or B cell), and the maturity of the cells. The staging is elaborated below:
B-cell ALL staging
B cells originate and mature inside the bone marrow. B cells play a key role in coordinating humoral immune response and developing antibodies against antigens that later turns into memory B cells after they have been activated by antigen interaction.
- Early pre-B ALL: It accounts to approximately 10% of ALL cases.
- Common ALL: 50% of ALL cases are staged in this category
- Pre-B ALL: About 10% of cases
- Mature B-cell ALL: It constitutes about 4% of ALL cases.
T-cell ALL staging
T cells originate in the bone marrow but mature in the thymus. They are responsible for cell-mediated immunity. There are several different subsets of T cells including Helper, Cytotoxic, Memory, Regulatory, Natural killer and Gamma Delta T cells. T- cell ALL staging is done as:
- Pre-T ALL: Accounting for about 5 - 10 % of cases
- Mature T-cell ALL: About 15 - 20 % of cases belong to this category.
Mortality rates for Acute Lymphoblastic Leukemia are higher in the elderly than in children. For most cases, treatment works well to cure ALL. The survival rate gives a fair idea of the number of patients who were treated successfully; however, these rates cannot predict the outcome of any particular patient as the outlook varies largely on the basis of subtype of ALL, overall health condition, age and several other factors.
Here is the 5 year survival rate statistics based on the age groups of the patients:
|Age group||5 year Survival Rate|
|14 or less||90%|
|65 and above||15%|
Diagnosis is identifying and understanding the nature of the disease. Based on the findings such as age of the patient, stage of the disease, other cytogenetic parameters and primary response or relapse the doctors would design the optimum therapy. These have a reflection on the Prognosis or the outcome of therapy.
Early diagnosis of cancer makes the treatment easier and has a better outlook. However, for most types of cancer early diagnosis turns out to be a bit tricky as the cancer may not give out any sign or symptom till it reaches a pressing stage where it starts impacting the functionality of one of more organs. So, it is advised to go for regular screening tests for early detection of some cancers even when there are no prominent symptoms.
In case of Acute Lymphoblastic Leukemia the scenario is a bit different. Currently, there are no special tests that could ascertain its early detection. As the name suggests, it is acute which means the cancer cells have a tendency to spread out at a very fast pace. The best way to find leukemia early is to report any possible signs or symptoms immediately. People having a higher risk of ALL should be more alert and vigilant and should go for regular medical checkups.
Some of the general tests that are conducted to detect leukemic cells are discussed below:
Physical Examination and Medical History: This is the first step of diagnosing leukemia. The patient may visit for a regular health check up or to consult regarding the symptoms of the disease. During the physical examination, the overall health record of the patient is taken into account and any sign of unusual swollen glands or lumps is checked. If the person appears pale or complains about any of the mentioned symptoms then the doctor suspects leukemia.
Blood Tests: Since leukaemia is the cancer of the blood, a blood test can be helpful in getting a lot of information. Blood test is done to check the following parameters:
A complete blood count gives the following details:
- The amount of hemoglobin.
- The number of red blood cells.
- The portion of the sample made up of red blood cells.
- The number and type of white blood cells.
- The number of Platelets.
Usually, patients with ALL show lower red blood cells and platelets.
- Blood Chemistry: Oncologists may ask for some tests such as lipid profile as it has been shown to be abnormal in Childhood ALL patients.
- A peripheral blood smear examines the cells within the blood and checks the number of immature white cells. The blood smear sample can also be used for
- Cytogenetic analysis, which identifies certain changes in the number and size of chromosomes within cells.
- Immunophenotyping: identifies antigens or markers on the surface of a blood or bone marrow cell. The cells are also checked to confirm if the lymphocytes or myeloid are involved in malignancy and their subtype e.g. B lymphocytes or T lymphocytes.
Bone Marrow Tests
Bone marrow tests are helpful in confirming the presence of ALL along with giving details like the subtype and stage of ALL. It is done by inserting a hollow needle into the hipbone or breastbone that is done in two steps:
- A bone marrow aspiration to remove a liquid marrow sample
- A bone marrow biopsy to remove a small amount of bone filled with marrow
The extracted sample is checked under a powerful microscope to look for signs of cancer such as presence or absence of Philadelphia Chromosome.
Lymph node biopsy
Removing a lymph node or part of a lymph node is often done to help diagnose lymphomas, but this is rarely done in case of suspected ALL as the diagnosis is usually made looking at blood and bone marrow. Imaging tests
As leukemia does not form tumors, imaging tests aren’t as useful as they are for other types of cancer. However, imaging tests like CT scan, X- ray, MRI may be performed to detect infections or other problems, rather than for the leukemia itself. These imaging tests may use radioactive particles to highlight the spread of cancer cells. Imaging tests also give a fair idea of the extent of the disease.
Spinal fluid may be withdrawn for checking presence of leukemia cells under microscope for spread of malignancy in the Cerebro-spinal fluid.
In case of childhood ALL the following parameters are considered to predict the response to the designed treatment.
- The number of white blood cells in the blood at the time of diagnosis.
- Age at the time of diagnosis, weight at diagnosis and during treatment, sex, race, and ethnic background of the patient.
- Quicker or slower reduction in leukemic cell number after initiation of therapy.
- Type of leukemia e.g. B lymphocyte or T lymphocyte Leukemia.
- Presence or absence of Philadelphia Chromosome.
- Whether the child has Down syndrome.
- Whether leukemia cells are found in the cerebrospinal fluid.
Apart from the above factors, treatment options also depend on:
- Whether it is a standard-risk, high-risk or very high–risk ALL.
- Prior steroids therapy at induction therapy.
- How quickly and how low the leukemia cell count drops during treatment.
The treatment of ALL mainly focuses on:
- Killing leukemia cells
- Returning blood counts to normal
- Ridding the body of any signs of the disease
The treatment of childhood ALL usually has three phases. The fourth phase is CNS Directed therapy to prevent metastases to brain.
- Intensive/Remission Phase: This is the first phase of treatment. The goal is to kill the leukemia cells in the blood and bone marrow. This puts the leukemia into remission.
- Consolidation /intensification: This is the second phase of treatment. It begins once the leukemia is in remission. It aims to kill any leukemia cells present in the body and may cause a relapse.
- Maintenance: The third phase of treatment aims at killing any remaining leukemia cells that may re-grow and cause a relapse. Often the doses are lowered in this phase than used during the remission induction and consolidation phases.
- CNS Directed Therapy is used to prevent metastases to the brain
Some of the most common treatment approach for ALL includes:
Induction therapy is done to achieve remission, which means treating the patients by addressing all signs and symptoms related to ALL. Remission allows normal marrow cells to develop and the patient’s blood counts to return to normal levels. Generally, if blast cells are still evident after the first course of induction chemotherapy, a second course of chemotherapy, using different drugs, is given. Induction therapy is usually done over four to six weeks.
- Chemotherapy: As in ALL the leukemic cells show rapid growth, most patients need to start chemotherapy soon after diagnosis. Chemotherapy is the process of using anticancer drugs to control the growth of cancer cells. Thses drugs can be either consumed orally or may be injected directly into the viens. Some of the chemotherapeutic drugs used for treatment of ALL are:
- daunorubicin or doxorubicin
- L-asparaginace or PEG-L-asapraginase
- methoterate oral / methotrexate
- Targeted therapy: Targeted therapy refers to the use of drugs that target specific parts of cancer cells and tend to have less severe side effects. They can be used instead of or along with chemo in some situations. Some examples of targeted drugs are alemtuzumab and rituximab.
- Radiation therapy: This involves the use of high-energy radiation to kill cancer cells.
- A bone marrow transplant: This involves use of high doses of chemotherapy and radiation followed by a transplant of bone-forming stem cells. Stem cells usually come from a donor, or less likely, from your own bone marrow or peripheral blood.
Post remission Therapy
Once the induction therapy is completed, there should be no signs of leukemic cells in the body. However, further treatment is usually conducted to make sure that ALL does not recur.
Post-remission therapy consists of intensification therapy and maintenance therapy.
- Consolidation therapy is usually given in cycles for four to six months.
- Maintenance therapy is usually given for about two years.
Central Nervous System Prophylaxis
The ALL cells may have spread to the lining of the spinal cord and brain. A spinal tap is used to check the spinal fluid for ALL cells.
Allogeneic Stem Cell Transplantation
Allogeneic stem cell transplantation involves transferring stem cells from a healthy person (the donor) to the patient. The procedure follows high-intensity chemotherapy, potent drugs that must be toxic enough to kill leukemic cells.
The goals of an allogeneic transplant are to:
- Restore the body’s ability to make normal blood cells after high-dose chemotherapy
- Cure the patient of his or her ALL by killing any remaining ALL cells.
Reduced-Intensity Allogeneic Stem Cell Transplantation
A reduced-intensity allogeneic transplant uses lower doses of chemotherapy than a standard allogeneic transplant; it does not completely inactivate the patient’s immune system or treat the ALL as aggressively. This is beneficial for older and sicker patients.
Autologous Stem Cell Transplantation
An autologous transplant uses the patient’s own stem cells. It is not commonly used to treat ALL because of the high relapse rate.
Early diagnosis followed by well planned therapy improves chances of successful outcome. However, like other cancers sometimes the leukemic cells do not respond to the therapy. Such naturally resistant cancer is described as Refractory.
The treatment for ALL, involves some high intensity procedures such as stem cell transplant, chemotherapies and radiations to kill the leukemic cells and inhibit their growth. These medicines and radiations may result in several side effects. It is important to report any such side effect immediately.
ALL affects the ability of the bone marrow to produce adequate numbers of blood cells and platelets, and chemotherapy reduces this ability even further. Blood counts generally fall within a week of treatment and may take some time to recover, depending on the type and doses of drugs used. During this time, there is likely to be a need for antibiotics and other drugs to treat, or prevent infection. There is also likely to be a need for blood transfusions to treat severe anaemia, and platelet transfusions to reduce the risk of bleeding.
Other possible side-effects of chemotherapy include:
- Feeling sick - nausea and/or vomiting.
- Fatigue and constant weakness.
- hair loss and thinning
- mouth problems such as mucositis or ulcers
- diarrhoea or constipation
- skin problems such as dryness, rash or sensitivity to sunlight
- fertility problems
Side-effects of steroids depend largely on how long they are used for, and the dose. Short-term use may cause increased appetite, restlessness or difficulty sleeping. Longer-term use may lead to fluid retention, raised blood sugars and increased susceptibility to infections.
There is likelihood of recurrence of cancer after a period of time. This is called Relapse. It may happen in the blood and bone marrow, brain, spinal cord, testicles, or other parts of the body. In case of ALL, there is a risk of the leukemic cells entering the cerebro-spinal fluid further leading to brain metastases.
Childhood ALL is a curable disease, aggressive therapy is planned to prevent metastases to testes and bone marrow, which are difficult to treat while that to brain is almost fatal. Hence the treatment protocol incorporates special CNS directed therapy to prevent brain metastases.
Going for regular checkups and being attentive to even the slightest of health hazards may prove to be a life saving habit.