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ALL (also called acute lymphocytic leukemia) is an aggressive type of leukemia characterized by the presence of too many lymphoblasts or lymphocytes in the bone marrow and peripheral blood. It can spread to the lymph nodes, spleen, liver, central nervous system (CNS), and other organs. Without treatment, ALL usually progresses quickly.
Signs and symptoms of ALL may include the following:
ALL occurs in both children and adults. It is the most common type of cancer in children, and treatment results in a good chance for a cure. For adults, the prognosis is not as optimistic. This summary discusses ALL in adults. (Refer to the PDQ summary on Childhood Acute Lymphoblastic Leukemia Treatment for more information about ALL in children.)
Incidence and Mortality
Estimated new cases and deaths from ALL in the United States in 2014:
ALL presumably arises from malignant transformation of B- or T-cell progenitor cells. It is more commonly seen in children, but can occur at any age. The disease is characterized by the accumulation of lymphoblasts in the marrow or in various extramedullary sites, frequently accompanied by suppression of normal hematopoiesis. B- and T-cell lymphoblastic leukemia cells express surface antigens that parallel their respective lineage developments. Precursor B-cell ALL cells typically express CD10, CD19, and CD34 on their surface along, with nuclear terminal deoxynucleotide transferase (TdT), while precursor T-cell ALL cells commonly express CD2, CD3, CD7, CD34, and TdT.
Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.
It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is cytogenetically indistinguishable from the Philadelphia chromosome (Ph1). The Ph1 occurs in only 1% to 2% of patients with acute myeloid leukemia (AML), but it occurs in about 20% of adults and a small percentage of children with ALL. In the majority of children and in more than one-half of adults with Ph1-positive ALL, the molecular abnormality is different from that in Ph1-positive chronic myelogenous leukemia (CML).
Many patients who have molecular evidence of the bcr-abl fusion gene, which characterizes the Ph1, have no evidence of the abnormal chromosome by cytogenetics. The bcr-abl fusion gene may be detectable only by fluorescence in situ hybridization (FISH) or reverse-transcriptase polymerase chain reaction (RT-PCR) because many patients have a different fusion protein from the one found in CML (p190 vs. p210). These tests should be performed, whenever possible, in patients with ALL, especially in those with B-cell lineage disease.
L3 ALL is associated with a variety of translocations that involve translocation of the c-myc proto-oncogene to the immunoglobulin gene locus t(2;8), t(8;12), and t(8;22).
Patients with ALL may present with a variety of hematologic derangements ranging from pancytopenia to hyperleukocytosis. In addition to a history and physical, the initial workup should include:
A bone marrow biopsy and aspirate are routinely performed even in T-cell ALL to determine the extent of marrow involvement. Malignant cells should be sent for conventional cytogenetic studies, as detection of the Ph1 t(9;22), myc gene rearrangements (in Burkitt leukemia), and MLL gene rearrangements add important prognostic information. Flow cytometry should be performed to characterize expression of lineage-defining antigens and allow determination of the specific ALL subtype. In addition, for B-cell disease, the malignant cells should be analyzed using RT-PCR and FISH for evidence of the bcr-abl fusion gene. This last point is of utmost importance, as timely diagnosis of Ph1 ALL will significantly change the therapeutic approach.
Diagnostic confusion with AML, hairy cell leukemia, and malignant lymphoma is not uncommon. Proper diagnosis is crucial because of the difference in prognosis and treatment of ALL and AML. Immunophenotypic analysis is essential because leukemias that do not express myeloperoxidase include M0 AML, M7 AML, and ALL.
The examination of bone marrow aspirates and/or biopsy specimens should be done by an experienced oncologist, hematologist, hematopathologist, or general pathologist who is capable of interpreting conventional and specially stained specimens.
Prognosis and Survival
Factors associated with prognosis in patients with ALL include the following:
Two other chromosomal abnormalities with poor prognosis are t(4;11), which is characterized by rearrangements of the MLL gene and may be rearranged despite normal cytogenetics, and t(9;22). In addition to t(4;11) and t(9;22), compared with patients with a normal karyotype, patients with deletion of chromosome 7 or trisomy 8 have been reported to have a lower probability of survival at 5 years. In a multivariate analysis, karyotype was the most important predictor of disease-free survival.[Level of evidence: 3iiDii]
Late Effects of Treatment for Adult ALL
Long-term follow-up of 30 patients with ALL in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of ALL or AML younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.
The following leukemic cell characteristics are important:
In adults, French-American-British (FAB) L1 morphology (more mature-appearing lymphoblasts) is present in fewer than 50% of patients, and L2 morphology (more immature and pleomorphic) predominates. L3 (Burkitt) ALL is much less common than the other two FAB subtypes. It is characterized by blasts with cytoplasmic vacuolizations and surface expression of immunoglobulin, and the bone marrow often has an appearance described as a "starry sky" owing to the presence of numerous apoptotic cells. L3 ALL is associated with a variety of translocations that involve translocation of the c-myc proto-oncogene to the immunoglobulin gene locus t(2;8), t(8;12), and t(8;22).
Some patients presenting with acute leukemia may have a cytogenetic abnormality that is morphologically indistinguishable from the Philadelphia chromosome (Ph1). The Ph1 occurs in only 1% to 2% of patients with acute myeloid leukemia (AML), but it occurs in about 20% of adults and a small percentage of children with ALL. In the majority of children and in more than one-half of adults with Ph1-positive ALL, the molecular abnormality is different from that in Ph1-positive chronic myelogenous leukemia (CML).
Many patients who have molecular evidence of the bcr-abl fusion gene, which characterizes the Ph1, have no evidence of the abnormal chromosome by cytogenetics. The bcr-abl fusion gene may be detectable only by pulsed-field gel electrophoresis or reverse-transcriptase polymerase chain reaction for the bcr-abl fusion gene because many patients have a different fusion protein from the one found in CML (p190 vs. p210).
Using heteroantisera and monoclonal antibodies, ALL cells can be divided into several subtypes (see Table 1 ).[1,4,5,6]
About 95% of all types of ALL (except Burkitt, which usually has an L3 morphology by the FAB classification) have elevated terminal deoxynucleotidyl transferase (TdT) expression. This elevation is extremely useful in diagnosis; if concentrations of the enzyme are not elevated, the diagnosis of ALL is suspect. However, 20% of cases of AML may express TdT; therefore, its usefulness as a lineage marker is limited. Because Burkitt leukemias are managed according to different treatment algorithms, it is important to specifically identify these cases prospectively by their L3 morphology, absence of TdT, and expression of surface immunoglobulin. Patients with Burkitt leukemias will typically have one of the following three chromosomal translocations:
There is no clear-cut staging system for this disease. This disease is classified as untreated, in remission, or recurrent.
Untreated Adult ALL
For a newly diagnosed patient with no prior treatment, untreated adult ALL is defined by the following:
Adult ALL in Remission
A patient who has received remission-induction treatment of ALL is in remission if all of the following criteria are met:
Successful treatment of ALL consists of the control of bone marrow and systemic disease and the treatment (or prevention) of sanctuary-site disease, particularly the central nervous system (CNS).[1,2] The cornerstone of this strategy includes systemically administered combination chemotherapy with CNS preventive therapy. CNS prophylaxis is achieved with chemotherapy (intrathecal and/or high-dose systemic therapy) and, in some cases, cranial radiation therapy.
Treatment is divided into the following three phases:
The average length of treatment for ALL varies between 1.5 and 3 years in the effort to eradicate the leukemic cell population. Younger adults with ALL may be eligible for selected clinical trials for childhood ALL. (Refer to the PDQ summary on Childhood Acute Lymphoblastic Leukemia Treatment for more information.)
Entry into a clinical trial is highly desirable to assure adequate patient treatment and maximal information retrieval from the treatment of this highly responsive, but usually fatal, disease.
Standard Treatment Options for Untreated Adult ALL
Standard treatment options for untreated adult ALL include the following:
Remission induction therapy
Sixty percent to 80% of adults with ALL usually achieve a complete remission (CR) status following appropriate induction therapy. Appropriate initial treatment, usually consisting of a regimen that includes the combination of vincristine, prednisone, and an anthracycline, with or without asparaginase, results in a CR rate of up to 80%. In patients with Ph1-positive ALL, the remission rate is generally greater than 90% when standard induction regimens are combined with Bcr-abl tyrosine kinase inhibitors. In the largest study published to date of Ph1-positive ALL patients, overall survival (OS) for 1,913 adult ALL patients was 39% at 5 years.
Patients who experience a relapse after remission usually die within 1 year, even if a second CR is achieved. If there are appropriate available donors and if the patient is younger than 55 years, bone marrow transplantation may be a consideration in the management of this disease. Transplant centers performing five or fewer transplants annually usually have poorer results than larger centers. If allogeneic transplant is considered, transfusions with blood products from a potential donor should be avoided, if possible. [4,5,6,7,8,9,10]
Most current induction regimens for patients with adult ALL include combination chemotherapy with prednisone, vincristine, and an anthracycline. Some regimens, including those used in a Cancer and Leukemia Group B (CALGB) study (CLB-8811), also add other drugs, such as asparaginase or cyclophosphamide. Current multiagent induction regimens result in complete response rates that range from 60% to 90%.[1,4,5,11,12]
Imatinib mesylate is often incorporated into the therapeutic plan for patients with Ph1-positive ALL. Imatinib mesylate, an orally available inhibitor of the BCR-ABL tyrosine kinase, has been shown to have clinical activity as a single agent in Ph1-positive ALL.[13,14][Level of evidence: 3iiiDiv] More commonly, particularly in younger patients, imatinib is incorporated into combination chemotherapy regimens. There are several published single-arm studies in which CR rate and survival are compared with historical controls.
Evidence (Imatinib mesylate):
Several studies have suggested that the addition of imatinib to conventional combination chemotherapy induction regimens results in complete response rates, event-free survival rates, and OS rates that are higher than those in historical controls.[15,16,17] At the present time, no conclusions can be drawn regarding the optimal imatinib dose or schedule.
In each of these studies, common toxicities were nausea and liver enzyme abnormalities, which necessitated interruption and/or dose reduction of imatinib.[13,14] (Refer to the PDQ summary on Nausea and Vomiting for more information.) Subsequent allogeneic transplant does not appear to be adversely affected by the addition of imatinib to the treatment regimen.
Imatinib is generally incorporated into the treatment of patients with Ph1-positive ALL because of the responses observed in monotherapy trials. If a suitable donor is available, allogeneic bone marrow transplantation should be considered because remissions are generally short with conventional ALL chemotherapy clinical trials.
Since myelosuppression is an anticipated consequence of both leukemia and its treatment with chemotherapy, patients must be closely monitored during remission induction treatment. Facilities must be available for hematological support and for the treatment of infectious complications.
Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions, when appropriate.[19,20]
Evidence (Supportive care):
Empiric broad-spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic.[23,24] Careful instruction in personal hygiene and dental care and in recognizing early signs of infection are appropriate for all patients. Elaborate isolation facilities, including filtered air, sterile food, and gut flora sterilization, are not routinely indicated but may benefit transplant patients.[25,26]
Rapid marrow ablation with consequent earlier marrow regeneration decreases morbidity and mortality. White blood cell transfusions can be beneficial in selected patients with aplastic marrow and serious infections that are not responding to antibiotics. Prophylactic oral antibiotics may be appropriate in patients with expected prolonged, profound granulocytopenia (<100/mm3 for 2 weeks), though further studies are necessary. Serial surveillance cultures may be helpful in detecting the presence or acquisition of resistant organisms in these patients.
As suggested in a CALGB study (CLB-9111), the use of myeloid growth factors during remission-induction therapy appears to decrease the time to hematopoietic reconstitution.[29,30]
CNS prophylaxis therapy
The early institution of CNS prophylaxis is critical to achieve control of sanctuary disease.
Special Considerations for B-Cell and T-Cell Adult ALL
Two additional subtypes of adult ALL require special consideration. B-cell ALL, which expresses surface immunoglobulin and cytogenetic abnormalities such as t(8;14), t(2;8), and t(8;22), is not usually cured with typical ALL regimens. Aggressive brief-duration high-intensity regimens, including those previously used in CLB-9251 (NCT00002494), that are similar to those used in aggressive non-Hodgkin lymphoma have shown high response rates and cure rates (75% CR; 40% failure-free survival).[31,32,33] Similarly, T-cell ALL, including lymphoblastic lymphoma, has shown high cure rates when treated with cyclophosphamide-containing regimens.
Whenever possible, patients with B-cell or T-cell ALL should be entered in clinical trials designed to improve the outcomes in these subsets. (Refer to the Burkitt Lymphoma/Diffuse Small Noncleaved-cell Lymphoma and Lymphoblastic lymphoma sections in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated adult acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Standard Treatment Options for Adult ALL in Remission
Standard treatment options for adult ALL in remission include the following:
Current approaches to postremission therapy for adult ALL include short-term, relatively intensive chemotherapy followed by any of the following:
Because the optimal postremission therapy for patients with ALL is still unclear, participation in clinical trials should be considered. (Refer to the B-cell (Burkitt) lymphoma section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)
Administration of the newer dose-intensive schedules can be difficult and should be performed by physicians experienced in these regimens at centers equipped to deal with potential complications. Studies in which continuation or maintenance chemotherapy was eliminated had outcomes inferior to those with extended treatment durations.[8,9] Imatinib has been incorporated into maintenance regimens in patients with Ph1-positive ALL.[10,11,12]
Evidence (Allogeneic and autologous BMT):
AlloBMT results in the lowest incidence of leukemic relapse, even when compared with a BMT from an identical twin (syngeneic BMT). This finding has led to the concept of an immunologic graft-versus-leukemia effect similar to graft-versus-host disease (GVHD). The improvement in DFS in patients undergoing alloBMT as primary postremission therapy is offset, in part, by the increased morbidity and mortality from GVHD, veno-occlusive disease of the liver, and interstitial pneumonitis.
The use of matched unrelated donors for alloBMT is currently under evaluation but, because of its current high treatment-related morbidity and mortality, it is reserved for patients in second remission or beyond. The dose of total-body radiation therapy administered is associated with the incidence of acute and chronic GVHD and may be an independent predictor of leukemia-free survival.[Level of evidence: 3iiB]
Evidence (B-cell ALL):
Aggressive cyclophosphamide-based regimens similar to those used in aggressive non-Hodgkin lymphoma have shown improved outcome of prolonged DFS for patients with B-cell ALL (L3 morphology, surface immunoglobulin positive).
The early institution of CNS prophylaxis is critical to achieve control of sanctuary disease. Some authors have suggested that there is a subgroup of patients at low risk for CNS relapse for whom CNS prophylaxis may not be necessary. However, this concept has not been tested prospectively.
Aggressive CNS prophylaxis remains a prominent component of treatment. This report, which requires confirmation in other cooperative group settings, is encouraging for patients with L3 ALL. Patients with surface immunoglobulin and L1 or L2 morphology did not benefit from this regimen. Similarly, patients with L3 morphology and immunophenotype, but unusual cytogenetic features, were not cured with this approach. A WBC count of less than 50,000 per microliter predicted improved leukemia-free survival in a univariate analysis.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult acute lymphoblastic leukemia in remission. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Standard Treatment Options for Recurrent Adult ALL
Standard treatment options for recurrent adult ALL include the following:
Patients with ALL who experience a relapse following chemotherapy and maintenance therapy are unlikely to be cured by further chemotherapy alone. These patients should be considered for reinduction chemotherapy followed by alloBMT.
Palliative radiation therapy
Low-dose palliative radiation therapy may be considered in patients with symptomatic recurrence either within or outside the central nervous system.
Patients with Ph1-positive ALL will often be taking imatinib at the time of relapse and thus will have imatinib-resistant disease. Dasatinib, a novel tyrosine kinase inhibitor with efficacy against several different imatinib-resistant BCR-ABL mutations, has been approved for use in Ph1-positive ALL patients who are resistant to or intolerant of imatinib. The approval was based on a series of trials involving patients with chronic myelogenous leukemia, one of which included small numbers of patients with lymphoid blast crisis or Ph1-positive ALL.
Treatment Options Under Clinical Evaluation for Recurrent Adult ALL
Patients for whom an HLA-matched donor is not available are excellent candidates for enrollment in clinical trials that are studying the following:[3,4,5,6,7,8,9]
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent adult acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Adult Acute Lymphoblastic Leukemia
Updated statistics with estimated new cases and deaths for 2014 (cited American Cancer Society as reference 1).
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of acute lymphoblastic leukemia. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Adult Acute Lymphoblastic Leukemia Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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National Cancer Institute: PDQ® Adult Acute Lymphoblastic Leukemia Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/adultALL/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2014-02-21
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