Author: Dr Frederick Appelbaum Fred Hutchinson Cancer Research Center Seattle 2008-07-28
Acute Lymphocytic Leukemia (ALL)
ALL is less common than AML, occurring in an estimated 4000 persons in the United States in 2006. It is the most common form of leukemia in childhood, following which the incidence drops until the age of 45, when the incidence begins to increase. Like AML, ALL is rapidly fatal if untreated. With appropriate treatment, most children with ALL can be cured of their disease.Biology and Classification
As in AML, cytogenetic abnormalities are found in the majority of cases of ALL. These are listed in Table 2 along with their incidence and implications. Immunophenotyping is also of use in the diagnosis and classification of ALL; most cases have B-cell markers on their surface, but up to 25% will have T-cell markers. The distinction between B-cell and T-cell ALL may be of some importance in the selection of therapies. ALL is sometimes classified by its appearance into three subgroups, L1, L2 and L3. However, after accounting for molecular and immunologic findings, classification by morphology is of little clinical or scientific use.Table 2 Common Cytogenetic Abnormalities in ALL
| Abnormality | Incidence | Significance |
| 9p- | 9% | Favorable risk |
| 6q- | 7% | Intermediate risk |
| t(4;11) | 7% | Unfavorable risk |
| t(9;22) | 19% | Unfavorable risk, different treatment |
Causes of ALL
As for AML, in the vast majority of cases of ALL, no cause can be found. Prior exposure to radiation used to treat other diseases increases the risks of development of ALL. Very few other associations have been discovered, despite intensive investigations. ALL is not hereditary, nor is it contagious.Signs and Symptoms of ALL
The majority of signs and symptoms of ALL are due to failure of normal marrow function. Patients with ALL fail to make sufficient red cells and so are anemic, resulting in pallor, fatigue, headache, shortness of breath or a racing pulse with exertion, and dizziness upon standing. A lack of normal white cell production can lead to recurrent infections causing fever, night sweats or non-healing skin sores. Insufficient platelet production can result in easy bruising, petechiae, gum bleeding or prolonged bleeding from minor cuts. Other signs of ALL can be the result of the growth and infiltration of the leukemic cells themselves leading to diffuse boney aches, enlarged tonsils or swollen lymph nodes.Diagnosis of ALL
The diagnosis of ALL is usually first suggested by a complete blood count with an abnormality in the number or appearance of cells. Confirmation of the diagnosis requires a bone marrow examination. ALL sometimes infiltrates into the central nervous system (CNS) and can be found in the fluid around the brain (the cerebrospinal fluid). Thus, a spinal tap is frequently performed during initial evaluation to determine if there is CNS involvement, which can influence subsequent therapy.Treatment of ALL
Without treatment, ALL is a rapidly fatal disease, and so once the diagnosis is made, treatment should be begun as soon as possible. The type of treatment is influenced by patient age, extent of disease (for example, whether it has spread to the CNS), and the cytogenetic and molecular profile of the disease.Induction Chemotherapy
The initial goal of treatment of ALL is to induce a complete remission. Various drug regimens have been tested, and the most active generally include some combination of vincristine, prednisone, asparaginase, anthracyclines, and cyclophosphamide. There is currently insufficient evidence to state that any one regimen is superior to all others. There are several types of ALL where alternative regimens are often used. In patients with ALL with the Philadelphia chromosome (which is a specific translocation between chromosomes 9 and 22), adding imatinib, dasatinib, or nilotinib to the chemotherapy may be of benefit. [10] In patients with mature B-cell ALL (Burkitt’s leukemia), rituximab is often added to the initial chemotherapy. [11] Patients are usually hospitalized while receiving induction chemotherapy. Within days of starting therapy, most patients will have a severe drop in their red cell, white cell, and platelet counts. Patients then receive antibiotic and transfusion support until their blood counts recover, which can take several weeks, depending on the particular regimen used for initial treatment. With currently used regimens, complete responses are expected in approximately 85% of adults and 95% of children.Post-induction Therapy
There are three general forms of post-induction therapy for ALL: further chemotherapy, allogeneic HCT and autologous HCT. The choice of therapy is influenced by the age of the patient, the subtype of leukemia, the availability of an appropriate donor, and many other issues including the underlying health of the patient as well as the patient's treatment goals.Most children with ALL can be cured using a combination of consolidation chemotherapy, central nervous system treatment, and maintenance therapy. There are a number of different treatment regimens that have been successfully employed. In most, consolidation chemotherapy is made up of several cycles of chemotherapy similar in intensity to initial induction chemotherapy and which are composed of some of the same drugs used during induction, but often with others included as well. Chemotherapeutic agents given orally or intravenously do not penetrate well into the central nervous system because of a “blood/brain barrier.” Even if patients do not have central nervous system involvement at diagnosis, disease recurrence in the CNS will occur in up to one third of patients unless specific measures are taken to prevent this. Such CNS prophylaxis may include cranial irradiation, direct injection of chemotherapy into the cerebrospinal fluid via a lumbar tap, or intravenous administration of specific chemotherapies at very high doses, which causes then to cross into the CNS. Some form of CNS prophylaxis is used in virtually every ALL treatment protocol. Following consolidation chemotherapy and CNS prophylaxis, patients are generally treated with low dose maintenance chemotherapy for anywhere from 1 to 3 years, depending on patient risk factors and the particular treatment regimen chosen. Some children with very high risk ALL, as determined by cytogenetic tests showing t(9;22) or t(4:11), may benefit from allogeneic transplantation while in first remission. [12]
Post-remission therapy for adults age 17-60 may include many of the same elements as described for children, including consolidation chemotherapy, CNS prophylaxis and maintenance chemotherapy. However, even though the same therapies are used, cure rates of adult ALL are lower than seen in children, averaging around 40%. For this reason, studies have been conducted comparing standard chemotherapy with allogeneic or autologous transplantation. Allogeneic transplantation appears to offer a survival advantage, particularly for high risk patients as determined by cytogenetic risk grouping. There is little evidence to suggest that autologous transplantation in first remission is of benefit.