Acute lymphoblastic leukemia, also known as acute lymphocytic leukemia or acute lymphoid leukemia (ALL), is an acuteform of leukemia, or cancer of the white blood cells, characterized by the overproduction and accumulation of cancerous, immaturewhite blood cells, known as lymphoblasts. In persons with ALL, lymphoblasts are overproduced in the bone marrow and continuously multiply, causing damage and death by inhibiting the production of normal cells (such as red and white blood cells andplatelets) in the bone marrow and by spreading (infiltrating) to other organs. ALL is most common in childhood, with a peak incidence at 2–5 years of age and another peak in old age.
The symptoms of ALL are indicative of a reduced production of functional blood cells, because leukemia wastes the resources of thebone marrow that are normally used to produce new, functioning blood cells. These symptoms can include fever, increased risk of infection (especially bacterial infections like pneumonia, due to neutropenia; symptoms of such an infection include shortness of breath, chest pain, cough, vomiting, changes in bowel or bladder habits), increased tendency to bleed (due to thrombocytopenia), and signs indicative of anemia, including pallor, tachycardia (high heart rate), fatigue, and headache.
About 6,000 cases are reported in the United States every year. Internationally, ALL is more common in Caucasians than in Africans; it is more common in Hispanics and in Latin America.:1617 Cure is a realistic goal and is achieved in more than 80% of affected children, although only 20-40% of adults are cured. "Acute" refers to the relatively short time course of the disease, distinguishing it from chronic lymphocytic leukemia, which has a potential time course of many years.
ALL was one of the first cancers for which an effective chemotherapeutic treatment was developed. Antifolates like aminopterin andmethotrexate were developed in the late 1940s by Sidney Farber and Yellapragada Subbarow.At that time, a doctor did not need a patient's or parent's consent to try an experimental treatment as the Nuremberg code had not yet been signed. Desperate to save his patients, Farber initially tried folic acid supplementation as a treatment for ALL. This had disastrous consequences and he likely accelerated the children's deaths.
Signs and symptoms
Initial symptoms are not specific to ALL, but worsen to the point that medical help is sought. They result from the lack of normal and healthy blood cells because they are crowded out by malignant and immature leukocytes (white blood cells). Therefore, people with ALL experience symptoms from malfunctioning of their erythrocytes (red blood cells), leukocytes, and platelets. Laboratory tests that might show abnormalities include blood count tests, renal function tests, electrolyte tests, and liver enzyme tests.
The signs and symptoms of ALL are variable but follow from bone marrow replacement and/or organ infiltration.
- Generalized weakness and fatigue
- Anemia
- Dizziness
- Frequent or unexplained fever and infection
- Weight loss and/or loss of appetite
- Excessive and unexplained bruising
- Bone pain, joint pain (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
- Pitting edema (swelling) in the lower limbs and/or abdomen
- Petechiae, which are tiny red spots or lines in the skin due to low platelet levels
Treatment
The earlier ALL 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 in 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 will receive a combination of medications. There are no surgical options because of the body-wide distribution of the malignant cells. In general, cytotoxic chemotherapy for ALL combines multiple antileukemic drugs in various combinations. Chemotherapy for ALL consists of three phases: remission induction, intensification, and maintenance therapy.
| Phase | Description | Agents |
|---|---|---|
| Remission induction | The aim of remission induction is to rapidly kill most tumor cells and get the patient into remission. This is defined as the presence of less than 5% leukemic blasts in the bone marrow, normal blood cells and absence of tumor cells from blood, and absence of other signs and symptoms of the disease. Central nervous system (CNS) prophylaxis should begin during this phase of treatment and continue during the consolidation/intensification period. The rationale is based on the presence of CNS involvement in 10%-40% of adult patients at diagnosis. | Combination of prednisolone or dexamethasone, vincristine,asparaginase (better tolerance in pediatric patients), anddaunorubicin (used in Adult ALL) is used to induce remission. Central nervous system prophylaxis can be achieved via irradiation, cytarabine + methotrexate, or liposomal cytarabine.In Philadelphia chromosome-positive ALL, the intensity of initial induction treatment may be less than has been traditionally given. |
| Consolidation/intensification | Intensification uses high doses of intravenous multidrug chemotherapy to further reduce tumor burden. Since ALL cells sometimes penetrate the CNS, most protocols include delivery of chemotherapy into the CNS fluid (termedintrathecal chemotherapy). Some 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). Other centers would perform multiple lumbar punctures as needed for testing and treatment delivery. | Typical intensification protocols use vincristine, cyclophosphamide,cytarabine, daunorubicin, etoposide, thioguanine ormercaptopurine given as blocks in different combinations. For CNS protection, intrathecal methotrexate or cytarabine is usually used combined with or without cranio-spinal irradiation (the use of radiation therapy to the head and spine). Central nervous system relapse is treated with intrathecal administration of hydrocortisone, methotrexate, and cytarabine. |
| Maintenance therapy | The aim of maintenance therapy is to kill any residual cell that was not killed by remission induction and intensification regimens. Although such cells are few, they will cause relapse if not eradicated. | For this purpose, daily oral mercaptopurine, once weekly oralmethotrexate, once monthly 5-day course of intravenousvincristine and oral corticosteroids are usually used. The length of maintenance therapy is 3 years for boys, 2 years for girls and adults. |
As the chemotherapy regimens can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD, or CALGB protocols; for ALL, about 3 years, 2 months for males on COG protocols, and 2 years, 2 months for females — longer for males because the testicles are a potential reservoir), many patients have an intravenouscatheter inserted into a large vein (termed a central venous catheter or a Hickman line), or a Portacath, a cone-shaped port 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.
Radiation therapy
Radiation therapy (or radiotherapy) is used on painful bony areas, in high disease burdens, 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. Most specialists in adult leukemia have abandoned the use of radiation therapy for CNS prophylaxis, instead using intrathecal chemotherapy.
Biological therapy
For some subtypes of relapsed ALL, aiming at biological targets such as the proteasome, in combination with chemotherapy, has given promising results in clinical trials.Selection of biological targets on the basis of their combinatorial effects on the leukemic lymphoblasts can lead to clinical trials for improvement in the effects of ALL treatment.
In ongoing clinical trials, a CD19-CD3 bi-specific monoclonal murine antibody, blinatumomab, is showing great promise.
Immunotherapy
Chimeric antigen receptors (CARs) have been developed as a promising therapy for ALL. This technology uses a single chain variable fragment (scFv) designed to recognize the cell surface marker CD19 as a method of treating ALL. CD19 is a molecule found on all B-cells and can be used as a means of distinguishing the potentially malignant B-cell population in the patient. In this therapy, mice are immunized with the CD19 antigen and produce anti-CD19 antibodies. Hybridomas developed from the mouse spleen cells fused to a myeloma cell line can be developed as a source for the cDNA encoding the CD19 specific antibody. The cDNA is sequenced and the sequence encoding the variable heavy and variable light chains of these antibodies are cloned together using a small peptide linker. This resulting sequence encodes the scFv. This can be cloned into a transgene encoding what will become the endodomain of the CAR. There are varying arrangements of subunits used as the endodomain but they generally consist of the hinge region that attaches to the scFv, a transmembrane region, the intracellular region of a costimulatory molecule such as CD28, and the intracellular domain of CD3-zeta containingITAM repeats. Other sequences frequently included are: 4-1bb and OX40. The final transgene sequence, containing the scFv and endodomain sequences is then inserted into immune effector cells that are obtained from the patient and expanded in vitro. In previous trials these have been a type of T-cell capable of cytotoxicity. Inserting the DNA into the effector cell can be accomplished by several methods. Most commonly, this is done using a lentivirus which encodes the transgene. Pseudotyped, self-inactivating lentiviruses have been shown to be an effective method for the stable insertion of a desired transgene into the target cell genomic DNA. Other methods include electroporation and transfection but these are limited in their efficacy as transgene expression will diminish over time. The gene-modified effector cells are then transplanted back into the patient. Typically this process is done in conjunction with a conditioning regimen such as cyclophosphamide which has been shown to potentiate the effects of infused T-cells. This effect has been attributed to making an immunologic space within which the cells populate. The process as a whole results in an effector cell, typically a T-cell, that can recognize a tumor cell antigen in a manner that is independent of the major histocompatibility complex, and which can initiate a cytotoxic response.
Pregnancy
Leukemia is rarely associated with pregnancy, affecting only about 1 in 10,000 pregnant women. How it is handled depends primarily on the type of leukemia. Acute leukemias normally require prompt, aggressive treatment, despite significant risks of pregnancy loss and birth defects, especially if chemotherapy is given during the developmentally sensitive first trimester.
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