National Cancer Institute
Last Modified: June 3, 2003
Sixty percent to 80% of adults with acute lymphoblastic leukemia (ALL) can be expected to attain complete remission status following appropriate induction therapy. Approximately 35% to 40% of adults with ALL can be expected to survive 2 years with aggressive induction combination chemotherapy and effective supportive care during induction therapy (appropriate early treatment of infection, hyperuricemia, and bleeding). A few studies that use intensive multiagent approaches suggest that a 50% 3-year survival is achievable in selected patients, but these results must be verified by other investigators. 1 2 3 4
As in childhood ALL, adult patients with ALL are at risk of developing central nervous system (CNS) involvement during the course of their disease. This is particularly true for patients with L3 histology. 5 Both treatment and prognosis are influenced by this complication. 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. Diagnostic confusion with acute myelocytic leukemia (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 and M7 AML as well as ALL.
Appropriate initial treatment, usually consisting of a regimen that includes the combination of vincristine, prednisone, and anthracycline, with or without asparaginase, results in a complete remission rate of up to 80%. Median remission duration for the complete responders is approximately 15 months. Entry into a clinical trial is highly desirable to assure adequate patient treatment and also maximal information retrieval from the treatment of this highly responsive, but usually fatal, disease. Patients who experience a relapse after remission can be expected to succumb within 1 year, even if a second complete remission is achieved. If there are appropriate available donors and if the patient is younger than 55 years of age, bone marrow transplantation may be a consideration in the management of this disease. 6 Transplant centers performing 5 or fewer transplants annually usually have poorer results than larger centers. 7 If allogeneic transplant is considered, transfusions with blood products from a potential donor should be avoided if possible. 4 8 9 10 11 12 13
Patients with L3 morphology have improved outcomes when treated according to specific treatment algorithms. 14 15 Age, which is a significant factor in childhood ALL and in AML, may also be an important prognostic factor in adult ALL. In one study, overall the prognosis was better in patients younger than 25 years; another study found a better prognosis in those younger than 35 years. These findings may, in part, be related to the increased incidence of the Philadelphia chromosome (Ph1) in older ALL patients, a subgroup associated with poor prognosis. 1 2 Elevated B2-microglobulin is associated with a poor prognosis in adults as evidenced by lower response rate, increased incidence of CNS involvement, and significantly worse survival. 16 Patients with Ph1-positive ALL are rarely cured with chemotherapy. 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. Because many patients have a different fusion protein from the one found in chronic myelogenous leukemia (p190 versus p210), the bcr-abl fusion gene may be detectable only by pulsed-field gel electrophoresis or reverse-transcriptase polymerase chain reaction (RT-PCR). These tests should be performed whenever possible in patients with ALL, especially those with B-cell lineage disease. Two other chromosomal abnormalities with poor prognoses 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(9;22) and t(4;11), patients with deletion of chromosome 7 or trisomy 8 have been reported to have a lower probability of survival at 5 years compared to patients with a normal karyotype. 17 L3 ALL is associated with a variety of translocations which involve translocation of the c-myc proto-oncogene to the immunoglobulin gene locus (t(2;8), t(8;12), and t(8;22)).
Long-term follow-up of 30 patients with ALL in remission for at least 10 years has demonstrated 10 cases of secondary malignancies. Of 31 long-term female survivors of ALL or acute myeloid leukemia under 40 years of age, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, 2 congenital problems occurred. 18
Leukemic cell characteristics including morphological features, cytochemistry, immunologic cell surface and biochemical markers, and cytogenetic characteristics are important. In adults, FAB L1 morphology (more mature appearing lymphoblasts) is present in fewer than 50% of patients and L2 histology (more immature and pleomorphic) predominates. 1 Chromosomal abnormalities including aneuploidy and translocations have been described and may correlate with prognosis. 2 In particular, patients with Philadelphia chromosome (Ph1)-positive t(9;22) acute lymphoblastic leukemia (ALL) have a poor prognosis and represent more than 30% of adult cases. The bcr-abl fusion gene resulting from the breakpoint in the Ph1 may, on occasion, be detectable only by pulse-field gel electrophoresis or reverse-transcriptase polymerase chain reaction. Bcr-abl rearranged leukemias that do not demonstrate the classical Ph1 carry a poor prognosis that is similar to those that are Ph1-positive.
Using heteroantisera and monoclonal antibodies, ALL cells can be divided into early B-cell lineage (80% approximate frequency), T-cells (10%-15% approximate frequency), B cells (with surface immunoglobulins), (<5% approximate frequency), and CALLA+ (common ALL antigen), 50% approximate frequency. 1 3 4 5
About 95% of all types of ALL except B cell (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 acute myeloid leukemia (AML) may express TdT; therefore, its usefulness as a lineage marker is limited. Because B-cell leukemias are treated according to different algorithms, it is important to specifically identify these cases prospectively by their L3 morphology, absence of TdT, and expression of surface immunoglobulin. These patients will typically have 1 of 3 chromosomal translocations: t(8;14), t(2;8), or t(8;22).
There is no clear-cut staging system for this disease.
For a newly diagnosed patient with no prior treatment, untreated adult acute lymphoblastic leukemia (ALL) is defined as an abnormal white blood cell count and differential, abnormal hematocrit/hemoglobin and platelet counts, abnormal bone marrow with more than 5% blasts, and signs and symptoms of the disease.
A patient who has received remission-induction treatment of ALL is in remission if the bone marrow is normocellular with less than 5% blasts, there are no signs or symptoms of the disease, no signs or symptoms of central nervous system leukemia or other extramedullary infiltration, and all of the following laboratory values are within normal limits: white blood cell count and differential, hematocrit/hemoglobin level, and platelet count.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Successful treatment of acute lymphoblastic leukemia (ALL) consists of the control of bone marrow and systemic disease as well as 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) and, in some cases, cranial irradiation.
Treatment is divided into 3 phases: remission induction, CNS prophylaxis, and remission continuation or maintenance. The average length of treatment of 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.
It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is morphologically indistinguishable from the Philadelphia chromosome (Ph1). 3 The Ph1 occurs in only 1% to 2% of patients with AML, but it occurs in about 20% of adults and a small percentage of children with ALL. 4 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).
Ph1-positive ALL has a worse prognosis than most other types of ALL, although many children and some adults with Ph1-positive ALL may have complete remissions following intensive ALL treatment clinical 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. 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. Because many patients have a different fusion protein from the one found in CML (p190 versus p210), the bcr-abl fusion gene may be detectable only by pulsed-field gel electrophoresis or reverse-transcriptase polymerase chain reaction (RT-PCR). These tests should be performed whenever possible in patients with ALL, especially those with B-cell lineage disease. 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(9;22) and t(4;11), patients with deletion of chromosome 7 or trisomy 8 have been reported to have a lower probability of survival at 5 years compared to patients with a normal karyotype. In multivariate analysis, karyotype was the most important predictor of disease-free survival. 5 [Level of evidence: 3iiDi] L3 ALL is associated with a variety of translocations which involve translocation of the c-myc proto-oncogene to the immunoglobulin gene locus (t(2;8), t(8;12), and t(8;22)). Unlike bcr-abl-positive ALL and t(4;11) ALL, there is some evidence that L3 leukemia can be cured with aggressive, rapidly cycling lymphoma-like chemotherapy regimens. 6 7 8
The designations in PDQ that treatments are standard or under clinical evaluation are not to be used as a basis for reimbursement determinations.
Standard treatment options for remission induction therapy:
Most current induction regimens for adult acute lymphoblastic leukemia (ALL) include prednisone, vincristine, and an anthracycline. Some regimens 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 2 3
Two 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 similar to those used in aggressive non-Hodgkin's lymphoma have shown high response rates and cure rates (75% complete remission; 40% failure-free survival). 4 5 T-cell ALL, including lymphoblastic lymphoma, similarly has shown high cure rates when treated with cyclophosphamide-containing regimens. 3 Whenever possible, such patients should be entered in clinical trials designed to improve the outcomes in these subsets. (Refer to the PDQ summary on Adult Non-Hodgkin's Lymphoma Treatment for more information on B-cell (Burkitt) lymphoma and T-cell (lymphoblastic) lymphoma.)
Since myelosuppression is an anticipated consequence of both the leukemia and its treatment with chemotherapy, patients must be closely monitored during remission induction treatment. Facilities must be available for hematological support as well as for the treatment of infectious complications.
Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions when appropriate. 6 7 Randomized trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000 per cubic millimeter rather than 20,000 per cubic millimeter. 8 The incidence of platelet alloimmunization was similar among groups randomly assigned to receive pooled platelet concentrates from random donors; filtered, pooled platelet concentrates from random donors; ultraviolet B-irradiated, pooled platelet concentrates from random donors; or filtered platelets obtained by apheresis from single random donors. 9 Empiric broad spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic. 10 11 Careful instruction in personal hygiene, dental care, and recognition of early signs of infection are appropriate in all patients. Elaborate isolation facilities, including filtered air, sterile food, and gut flora sterilization are not routinely indicated but may benefit transplant patients. 12 13 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. 14 Prophylactic oral antibiotics may be appropriate in patients with expected prolonged, profound granulocytopenia (<100 per cubic millimeter for 2 weeks), although further studies are necessary. 15 To detect the presence or acquisition of resistant organisms, serial surveillance cultures may be helpful in such patients. The use of myeloid growth factors during remission induction therapy appears to decrease the time to hematopoietic reconstitution. 16 17
Treatment options for remission induction therapy under clinical evaluation:
Standard treatment options for central nervous system (CNS) prophylaxis:
The early institution of CNS prophylaxis is critical to achieve control of sanctuary disease.
Current approaches to postremission therapy for adult acute lymphoblastic leukemia (ALL) include short-term, relatively intensive chemotherapy followed by longer-term therapy at lower doses (maintenance), high-dose marrow-ablative chemotherapy or chemoradiotherapy with allogeneic stem cell rescue (alloBMT), and high-dose therapy with autologous stem cell rescue (autoBMT). Several trials of aggressive postremission chemotherapy for adult ALL now confirm a long-term disease-free survival rate of approximately 40%. 1 2 3 4 5 In the latter 2 series, especially good prognoses were found for patients with T-cell lineage ALL, with disease-free survival rates of 50% to 70% for patients receiving postremission therapy. These series represent a significant improvement in disease-free survival rates over previous, less intensive chemotherapeutic approaches. In contrast, poor cure rates were demonstrated in patients with Philadelphia chromosome (Ph1)-positive ALL, B-cell lineage ALL with an L3 phenotype (surface immunoglobulin positive), and B-cell lineage ALL characterized by t(4;11). 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 were eliminated had outcomes inferior to those with extended treatment durations. 6 7
AlloBMT results in the lowest incidence of leukemic relapse, even when compared with a bone marrow transplant 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 disease-free survival 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. 8 The results of a retrospective study showed a similar outcome to that for intensive chemotherapy for patients receiving alloBMT in first remission in both the International Bone Marrow Transplant Registry and the German chemotherapy trial (Berlin-Frankfurt-Munster). 9 In a prospective French trial, adults with ALL in remission and who were younger than age 40 years received alloBMT if a sibling donor was available or were randomly assigned to either ongoing chemotherapy or autoBMT. There was no advantage to alloBMT for the group of patients with standard-risk ALL. 10 There was, however, significant survival benefit to alloBMT for patients with high-risk ALL (CD10-; B-cell lineage ALL with a white blood cell count >30,000; Ph1-positive ALL). This trial confirms the experience of a single institution that suggested the utility of alloBMT for the cure of high-risk ALL. 11 The long-term survival of patients in the French randomized study who received chemotherapy and autoBMT was identical. 12 The use of alloBMT as primary postremission therapy is limited both by the need for an HLA-matched sibling donor and by the increased mortality from alloBMT in patients in their 5th or 6th decade. The mortality from alloBMT using an HLA-matched sibling donor ranges from 20% to 40%, depending on the study. The use of matched unrelated donors for alloBMT is currently under evaluation but, because of its current high treatment-related morbidity and mortality, is reserved for patients in second remission or beyond. The dose of total body irradiation administered is associated with the incidence of acute and chronic GVHD and may be an independent predictor of leukemia-free survival. 13 [Level of evidence: 3iiB]
Aggressive cyclophosphamide-based regimens similar to those used in aggressive non-Hodgkin's lymphoma have shown improved outcome of prolonged disease-free status for patients with B-cell ALL (L3 morphology, surface immunoglobulin positive). 14 Retrospectively reviewing 3 sequential cooperative group trials from Germany, Hoelzer and colleagues found a marked improvement in survival, from zero survivors in a 1981 study that used standard pediatric therapy and lasted 2.5 years, to a 50% survival rate in 2 subsequent trials that used rapidly alternating lymphoma-like chemotherapy and were completed within 6 months. 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 but 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 white blood cell count of less than 50,000 per microliter predicted improved leukemia-free survival in univariate analysis. Because the optimal postremission therapy for patients with ALL is still unclear, participation in clinical trials should be considered. (Refer to the PDQ summary on Adult Non-Hodgkin's Lymphoma Treatment for more information on B-cell (Burkitt) lymphoma.)
Standard treatment options for central nervous system (CNS) prophylaxis:
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. 15
Patients 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 allogeneic bone marrow transplantation. Patients for whom an HLA-matched donor is not available are excellent candidates for enrollment in clinical trials that are studying autologous transplantation, immunomodulation, and novel chemotherapeutic or biological agents. 1 2 3 4 5 6 7 Low-dose palliative radiation therapy may be considered in patients with symptomatic recurrence either within or outside the central nervous system. 8
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.
Editorial changes were made to this summary.
This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).