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Acute lymphoblastic leukemia
Specialty	Oncology

Acute lymphoblastic leukemia (ALL), also known as acute lymphocytic leukemia, is a cancer of the white blood cells, characterised by the overproduction and continuous multiplication of malignant and immature white blood cells (referred to as lymphoblasts) in the bone marrow. It is a hematological malignancy. It is fatal if left untreated as ALL spreads into the bloodstream and other vital organs quickly. It mainly affects young children and adults over 50. Acute refers to the undifferentiated, immature state of the circulating lymphocytes ("blasts")

Symptoms

Initial symptoms of ALL are quite aspecific, but worsen to the point that medical help is sought. The signs and symptoms of ALL are variable but follow from bone marrow replacement and / or organ infiltration.

• Generalised weakness and fatigue
• Anemia
• Frequent or unexplained fever and infections
• Weight loss and/or loss of appetite
• Excessive bruising or bleeding from wounds, nosebleeds, petechiae (red pinpoints on the skin)
• Bone pain, joint pains (caused by the spread of "blast" cells to the surface of the bone or into the joint from the marrow cavity)
• Breathlessness
• Enlarged lymph nodes, liver and/or spleen

The signs and symptoms of ALL result from the lack of normal and healthy blood cells because they are crowded out by malignant and immature white blood cells. Therefore, people with ALL experience symptoms from their red blood cells, white blood cells, and platelets not functioning properly. Laboratory tests which might show abnormalities include blood counts, renal functions, electrolytes and liver enzymes.

Diagnosis

Diagnosing leukemia usually begins with a medical history and physical examination. If there is a suspicion of leukemia, the patient will then proceed to undergo a number of tests to establish the presence of leukemia and its type. Patients with this constellation of symptoms will generally have had blood tests, such as a full blood count.

These tests may include complete blood count (blasts on the blood film generally lead to the suspicion of ALL being raised). Nevertheless, 10% have a normal blood film, and clinical suspicion alone may be the only reason to perform a bone marrow biopsy, which is the next step in the diagnostic process.

Bone marrow is examined for blasts, cell counts and other signs of disease. Pathological examination, cytogenetics (e.g. presence of the Philadelphia chromosome) and immunophenotyping establish whether the "blast" cells began from the B lymphocytes or T lymphocytes.

If ALL has been established as a diagnosis, a lumbar puncture is generally required to determine whether the malignant cells have invaded the central nervous system (CNS).

Lab tests (mentioned above) and clinical information may also be used to determine whether other medical imaging (such as ultrasound or CT scanning) may be required to find invasion of other organs such as the lungs or liver.

Pathophysiology

The etiology of ALL remains uncertain although some doctors believe that ALL develops from a combination of genetic and environmental factors. However, there is no definite way of determining the cause of leukemia.

Scientific research has shown that all malignancies are due to subtle or less subtle changes in DNA that lead to unimpaired cell division and breakdown of inhibitory processes. In leukemias, including ALL, chromosomal translocations occur regularly. It is thought that most translocations occur before birth during fetal development. These translocations may trigger oncogenes to "turn on", causing unregulated mitosis where cells divide too quickly and abnormally, resulting in leukemia. There is little indication that propensity for ALL is passed on from parents to children.

There have been indications that excessive exposure to high dose radiation (such as that of nuclear reactors, notably Chernobyl, and the atomic bombs in Nagasaki and Hiroshima, Japan 1945) increases the risk of developing acute leukemia. There has also been inconclusive evidence suggesting that exposure to chemicals such as benzene can cause an increased risk for developing acute leukemia.

Classification

Subtyping of the various forms of ALL is done according to the FAB (French-American-British) classification, which is used for all acute leukemias (including acute myelogenous leukemia, AML). As ALL is not a solid tumour, the TxNxMx notation used in those cancers is of little use.

The FAB classification is:

• ALL-L1: small uniform cells
• ALL-L2: large varied cells
• ALL-L3: large varied cells with vacuoles (bubble-like features)

Note: The recent WHO International panel on ALL recommends that this classification be abandoned, since the morphological classification has no clinical or prognostic relevance. It instead advocates the use of the immunophenotypic classification mentioned below.

Each subtype is then further classified by determining the surface markers of the abnormal lymphocytes, called immunophenotyping. There are three main immunologic types: B-cell, pre-B cell and T-cell. Subtyping helps determine the prognosis and most appropriate treatment in treating ALL.

Some cytogenetic subtypes have a worse prognosis than others. These include:

• A translocation between chromosomes 9 and 22, known as the Philadelphia chromosome, occurs in about 20% of adult and 5% in pediatric cases of ALL.
• A translocation between chromosomes 4 and 11 occurs in about 4% of cases and is most common in infants under 12 months.
• Not all translocations of chromosomes carry a poorer prognosis. Some translocations are relatively favorable. For example, Hyperdiploidy (>50 chromosomes) is a good prognostic factor.

Treatment

The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting remission, defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include chemotherapy, steroids, radiation therapy, intensive combined treatments (including bone marrow or stem cell transplants), and growth factors.

Chemotherapy

Chemotherapy is the initial treatment of choice. Most ALL patients end up receiving a combination of different treatments. There are no surgical options, due to the body-wide distribution of the malignant cells.

As the chemotherapy regimens can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; about 3 years for males on COG protocols), many patients have an intravenous catheter inserted into a large vein (termed a central venous catheter or a Hickman line), or a Portacath (a cone-shaped pot with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath). Since ALL cells sometimes penetrate the Central Nervous System CNS, most protocols include delivery of chemotherapy into the CNS fluid. More advanced centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the CNS fluid and to extract CNS fluid for various tests). More traditional centers would perform multiple lumbar punctures as needed for testing and treatment delivery.

Radiation therapy

Radiation therapy is used on painful bony areas, in high disease burden, or as part of the preparations for a bone marrow transplant (total body irradiation). Radiation in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s ALL. Recent studies showed that CNS chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.

Epidemiology

The number of annual ALL cases in the US is roughly 4000, 3000 of which inflict children. ALL accounts for approximately 80 per cent of all childhood leukemia cases, making it the most common type of childhood cancer. It has a peak incident rate of 2-5 years old, decreasing in incidence with increasing age before increasing again at around 50 years old. ALL is slightly more common in males than females. There is an increased incidence in people with Down Syndrome, Fanconi's anemia, Bloom's syndrome, ataxia-telangiectasia, X-linked agammaglobulinemia and severe combined immunodeficiency.

Prognosis

Advancements in medical technology and research over the past four decades in the treatment of ALL has improved the overall prognosis significantly from a zero to 20-75 percent survival rate, largely due to the continuous development of clinical trials and improvements in bone marrow transplantation (BMT) and stem cell transplanation (SCT) technology.

It is worth noting that medical advances in the last years, both through matching the best treatment to the genetic characteristics of the blast cells and through the availability of new drugs, are not fully reflected in statistics that usually refer to five-year survival rates. Patients (and other readers of this article) should not be discouraged by general treatment success rates because individual results vary substantially depending on the large number of variables that affect treatment outcomes. For example, the Philadelphia chromosome subset of ALL mentioned above can now be treated with several drugs, the most notable of which is imatinib (Gleevec). For patients, like in other cancers, the success rate is either 100% or zero, rendering overall statistical rates meaningless. Patients can affect their outcome through their choice of experienced doctors and major medical centers. However the prognosis for ALL differs between individuals depending on a wide variety of factors:

• Sex: females tend to fare better than males.
• Ethnicity: Caucasians are more likely to develop acute leukemia than African-Americans, Asians and Hispanics and tend to have a better prognosis than non-Caucasians.
• Age at diagnosis: children between 1-10 years of age are most likely to be cured.
• White blood cell count at diagnosis of less than 50,000
• Whether the cancer has spread to the brain or spinal cord
• Morphological, immunological, and genetic subtypes
• Response of patient to initial treatment
• Genetic disorders such as Down's Syndrome

External links

• The Leukemia & Lymphoma Society - provides information about leukemia and related diseases, updates on current clinical trials, and discussion forums.
• Cancer Research UK - trains and supports scientists for cancer research, offers regional news about current research, and provides ways that individuals can become involved.
• Children's Cancer Web - a directory of children's cancer-related resources.
• The Centre for Cancer and Blood Disorders at Sydney Children’s Hospital provides information on cancers in children and adolescents, including Acute lymphoblastic leukemia.
• Children's Leukemia and Cancer Research Foundation (INC) (Australia) - provides funding for children's leukemia, especially to the Princess Margaret Hospital for Children .
• European LeukemiaNet
• Ped-Onc Resource Center - provides information on childhood ALL, including disease details (MRD, phenotypes, molecular characterization), a layman's list of current and past clinical trials, a collection of articles on the possible causes of ALL, a bibliography of journal articles, and links to sources of support for parents of children with ALL.
• Association of Cancer Online Resource (ACOR) Leukemia Links - provides links to information on leukemia, including ALL, primarily in adults.

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