Adult Acute Lymphoblastic Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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Adult Acute Lymphoblastic Leukemia Treatment

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult acute lymphoblastic leukemia. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

  • Prognostic factors.
  • Cellular classification.
  • Staging.
  • Treatment options by cancer stage.

This summary 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.

Some of the reference citations in the 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. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

General Information

Note: Estimated new cases and deaths from acute lymphoblastic leukemia (ALL; also called acute lymphocytic leukemia) in the United States in 2009: [1]

  • New cases: 5,760.
  • Deaths: 1,400.

Sixty percent to 80% of adults with 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, including a Cancer and Leukemia Group B study (CLB-8811), 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.[2,3,4,5]

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.[6] 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.[7] Transplant centers performing five or fewer transplants annually usually have poorer results than larger centers.[8] If allogeneic transplant is considered, transfusions with blood products from a potential donor should be avoided if possible.[5,9,10,11,12,13,14]

Patients with L3 morphology have improved outcomes, as evidenced in a Cancer and Leukemia Group B study (CLB-9251), when treated according to specific treatment algorithms.[15,16] 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.[2,3] 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.[17] 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 vs. 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.[18] 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).

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, two congenital problems occurred.[19]

References:

1. American Cancer Society.: Cancer Facts and Figures 2009. Atlanta, Ga: American Cancer Society, 2009. Also available online. Last accessed January 6, 2010.
2. Gaynor J, Chapman D, Little C, et al.: A cause-specific hazard rate analysis of prognostic factors among 199 adults with acute lymphoblastic leukemia: the Memorial Hospital experience since 1969. J Clin Oncol 6 (6): 1014-30, 1988.
3. Hoelzer D, Thiel E, Löffler H, et al.: Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71 (1): 123-31, 1988.
4. Zhang MJ, Hoelzer D, Horowitz MM, et al.: Long-term follow-up of adults with acute lymphoblastic leukemia in first remission treated with chemotherapy or bone marrow transplantation. The Acute Lymphoblastic Leukemia Working Committee. Ann Intern Med 123 (6): 428-31, 1995.
5. Larson RA, Dodge RK, Burns CP, et al.: A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 85 (8): 2025-37, 1995.
6. Kantarjian HM, Walters RS, Smith TL, et al.: Identification of risk groups for development of central nervous system leukemia in adults with acute lymphocytic leukemia. Blood 72 (5): 1784-9, 1988.
7. Bortin MM, Horowitz MM, Gale RP, et al.: Changing trends in allogeneic bone marrow transplantation for leukemia in the 1980s. JAMA 268 (5): 607-12, 1992.
8. Horowitz MM, Przepiorka D, Champlin RE, et al.: Should HLA-identical sibling bone marrow transplants for leukemia be restricted to large centers? Blood 79 (10): 2771-4, 1992.
9. Linker CA, Levitt LJ, O'Donnell M, et al.: Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood 78 (11): 2814-22, 1991.
10. Barrett AJ, Horowitz MM, Gale RP, et al.: Marrow transplantation for acute lymphoblastic leukemia: factors affecting relapse and survival. Blood 74 (2): 862-71, 1989.
11. Dinsmore R, Kirkpatrick D, Flomenberg N, et al.: Allogeneic bone marrow transplantation for patients with acute lymphoblastic leukemia. Blood 62 (2): 381-8, 1983.
12. Jacobs AD, Gale RP: Recent advances in the biology and treatment of acute lymphoblastic leukemia in adults. N Engl J Med 311 (19): 1219-31, 1984.
13. Doney K, Buckner CD, Kopecky KJ, et al.: Marrow transplantation for patients with acute lymphoblastic leukemia in first marrow remission. Bone Marrow Transplant 2 (4): 355-63, 1987.
14. Vernant JP, Marit G, Maraninchi D, et al.: Allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia in first complete remission. J Clin Oncol 6 (2): 227-31, 1988.
15. Lee EJ, Petroni GR, Schiffer CA, et al.: Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukemia group B study 9251. J Clin Oncol 19 (20): 4014-22, 2001.
16. Hoelzer D, Ludwig WD, Thiel E, et al.: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87 (2): 495-508, 1996.
17. Kantarjian HM, Smith T, Estey E, et al.: Prognostic significance of elevated serum beta 2-microglobulin levels in adult acute lymphocytic leukemia. Am J Med 93 (6): 599-604, 1992.
18. Wetzler M, Dodge RK, Mrózek K, et al.: Prospective karyotype analysis in adult acute lymphoblastic leukemia: the cancer and leukemia Group B experience. Blood 93 (11): 3983-93, 1999.
19. Micallef IN, Rohatiner AZ, Carter M, et al.: Long-term outcome of patients surviving for more than ten years following treatment for acute leukaemia. Br J Haematol 113 (2): 443-5, 2001.

Cellular Classification

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 one of three chromosomal translocations: t(8;14), t(2;8), or t(8;22).

References:

1. Brearley RL, Johnson SA, Lister TA: Acute lymphoblastic leukaemia in adults: clinicopathological correlations with the French-American-British (FAB) co-operative group classification. Eur J Cancer 15 (6): 909-14, 1979.
2. Chromosomal abnormalities and their clinical significance in acute lymphoblastic leukemia. Third International Workshop on Chromosomes in Leukemia. Cancer Res 43 (2): 868-73, 1983.
3. Hoelzer D, Thiel E, Löffler H, et al.: Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71 (1): 123-31, 1988.
4. Sobol RE, Royston I, LeBien TW, et al.: Adult acute lymphoblastic leukemia phenotypes defined by monoclonal antibodies. Blood 65 (3): 730-5, 1985.
5. Foon KA, Billing RJ, Terasaki PI, et al.: Immunologic classification of acute lymphoblastic leukemia. Implications for normal lymphoid differentiation. Blood 56 (6): 1120-6, 1980.

Stage Information

There is no clear-cut staging system for this disease.

UNTREATED

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.

IN REMISSION

A patient who has received remission-induction treatment of ALL is in remission if the bone marrow is normocellular with 5% or less 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.

Treatment Option Overview

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 radiation therapy.

Treatment is divided into three 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 acute myelocytic leukemia, 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, though many children and some adults with Ph1-positive ALL may have complete remissions following intensive ALL treatment clinical trials. Imatinib mesylate, an orally available inhibitor of the BCR-ABL tyrosine kinase, has been shown to have clinical activity as a single agent in this disease.[5,6][Level of evidence: 3iiiDiv] In one study, 10 patients with Ph1-positive ALL and 10 patients with CML lymphoid blast crisis were treated with doses of imatinib ranging from 300 mg to 1000 mg per day.[5] Of these 20 patients, 4 had complete hematologic remission and 10 had marrow responses. Responses were short lived, with the majority of these patients relapsing at a median of 58 days after the start of therapy. In another study, 48 patients with Ph1-positive ALL were treated with 400 mg to 800 mg of imatinib per day.[6] The overall response rate was 60%, with 9 out of 48 patients (19%) achieving a complete remission. The responses again were short, with a median duration of 2.2 months. While there are no randomized clinical trials comparing chemotherapy with or without imatinib for this disease, because of the responses observed in monotherapy trials, imatinib is generally incorporated into the treatment of patients with Ph1-positive ALL. 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 vs. 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.[7][Level of evidence: 3iiDii] 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 such as was found in a Cancer and Leukemia Group B study (CLB-9251) that L3 leukemia can be cured with aggressive, rapidly cycling lymphoma-like chemotherapy regimens.[8,9,10]

References:

1. Clarkson BD, Gee T, Arlin ZA, et al.: Current status of treatment of acute leukemia in adults: an overview of the Memorial experience and review of literature. Crit Rev Oncol Hematol 4 (3): 221-48, 1986.
2. Hoelzer D, Gale RP: Acute lymphoblastic leukemia in adults: recent progress, future directions. Semin Hematol 24 (1): 27-39, 1987.
3. Peterson LC, Bloomfield CD, Brunning RD: Blast crisis as an initial or terminal manifestation of chronic myeloid leukemia: a study of 28 patients. Am J Med 60(2): 209-220, 1976.
4. Secker-Walker LM, Cooke HM, Browett PJ, et al.: Variable Philadelphia breakpoints and potential lineage restriction of bcr rearrangement in acute lymphoblastic leukemia. Blood 72 (2): 784-91, 1988.
5. Druker BJ, Sawyers CL, Kantarjian H, et al.: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344 (14): 1038-42, 2001.
6. Ottmann OG, Druker BJ, Sawyers CL, et al.: A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100 (6): 1965-71, 2002.
7. Wetzler M, Dodge RK, Mrózek K, et al.: Prospective karyotype analysis in adult acute lymphoblastic leukemia: the cancer and leukemia Group B experience. Blood 93 (11): 3983-93, 1999.
8. Fenaux P, Lai JL, Miaux O, et al.: Burkitt cell acute leukaemia (L3 ALL) in adults: a report of 18 cases. Br J Haematol 71 (3): 371-6, 1989.
9. Reiter A, Schrappe M, Ludwig WD, et al.: Favorable outcome of B-cell acute lymphoblastic leukemia in childhood: a report of three consecutive studies of the BFM group. Blood 80 (10): 2471-8, 1992.
10. Lee EJ, Petroni GR, Schiffer CA, et al.: Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukemia group B study 9251. J Clin Oncol 19 (20): 4014-22, 2001.

Untreated Adult Acute Lymphoblastic Leukemia

STANDARD TREATMENT OPTIONS FOR REMISSION INDUCTION THERAPY:

Most current induction regimens for patients with adult acute lymphoblastic leukemia (ALL) include prednisone, vincristine, and an anthracycline. Some regimens, including a Cancer and Leukemia Group B 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%.[1,2,3]

Imatinib mesylate is often incorporated into the therapeutic plan for patients with Ph1-positive ALL. Several studies have suggested that the addition of imatinib results in complete response rates, event-free survival rates, and overall survival rates that are higher than those in historical controls. In each of these studies, common toxicities were nausea and liver enzyme abnormalities necessitating interruption and/or dose reduction of imatinib. (For more information on nausea, refer to the PDQ summary on Nausea and Vomiting.) Subsequent allogeneic transplant does not appear to be adversely affected by the addition of imatinib to the treatment regimen. At the present time, no conclusions can be drawn from these studies regarding which imatinib dose or schedule should be used.[4,5,6]

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 (such as CLB-9251) similar to those used in aggressive non-Hodgkin lymphoma have shown high response rates and cure rates (75% complete remission; 40% failure-free survival).[7,8] 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 B cell (Burkitt) lymphoma and T cell (lymphoblastic) lymphoma sections in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)

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.[9,10] Randomized trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000/mm3 rather than 20,000/mm3.[11] 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.[12] Empiric broad spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic.[13,14] 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.[15,16] 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.[17] Prophylactic oral antibiotics may be appropriate in patients with expected prolonged, profound granulocytopenia (<100/mm3 for 2 weeks), though further studies are necessary.[18] To detect the presence or acquisition of resistant organisms, serial surveillance cultures may be helpful in such patients. As suggested in a Cancer and Leukemia Group B study (CLB-9111), the use of myeloid growth factors during remission induction therapy appears to decrease the time to hematopoietic reconstitution.[19,20]

TREATMENT OPTIONS FOR REMISSION INDUCTION THERAPY UNDER CLINICAL EVALUATION:

  • Clinical trials are ongoing, and patients should be considered for these studies.

STANDARD TREATMENT OPTIONS FOR CENTRAL NERVOUS SYSTEM (CNS) PROPHYLAXIS:

The early institution of CNS prophylaxis is critical to achieve control of sanctuary disease.

1. Cranial radiation therapy plus intrathecal (IT) methotrexate.
2. High-dose systemic methotrexate and IT methotrexate without cranial therapy radiation.
3. IT chemotherapy alone.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References:

1. Hoelzer D, Thiel E, Löffler H, et al.: Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71 (1): 123-31, 1988.
2. Linker CA, Levitt LJ, O'Donnell M, et al.: Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood 78 (11): 2814-22, 1991.
3. Larson RA, Dodge RK, Burns CP, et al.: A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 85 (8): 2025-37, 1995.
4. Thomas DA, Faderl S, Cortes J, et al.: Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 103 (12): 4396-407, 2004.
5. Yanada M, Takeuchi J, Sugiura I, et al.: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 24 (3): 460-6, 2006.
6. Wassmann B, Pfeifer H, Goekbuget N, et al.: Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 108 (5): 1469-77, 2006.
7. Hoelzer D, Ludwig WD, Thiel E, et al.: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87 (2): 495-508, 1996.
8. Lee EJ, Petroni GR, Schiffer CA, et al.: Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukemia group B study 9251. J Clin Oncol 19 (20): 4014-22, 2001.
9. Slichter SJ: Controversies in platelet transfusion therapy. Annu Rev Med 31: 509-40, 1980.
10. Murphy MF, Metcalfe P, Thomas H, et al.: Use of leucocyte-poor blood components and HLA-matched-platelet donors to prevent HLA alloimmunization. Br J Haematol 62 (3): 529-34, 1986.
11. Rebulla P, Finazzi G, Marangoni F, et al.: The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. N Engl J Med 337 (26): 1870-5, 1997.
12. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. The Trial to Reduce Alloimmunization to Platelets Study Group. N Engl J Med 337 (26): 1861-9, 1997.
13. Hughes WT, Armstrong D, Bodey GP, et al.: From the Infectious Diseases Society of America. Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. J Infect Dis 161 (3): 381-96, 1990.
14. Rubin M, Hathorn JW, Pizzo PA: Controversies in the management of febrile neutropenic cancer patients. Cancer Invest 6 (2): 167-84, 1988.
15. Armstrong D: Symposium on infectious complications of neoplastic disease (Part II). Protected environments are discomforting and expensive and do not offer meaningful protection. Am J Med 76 (4): 685-9, 1984.
16. Sherertz RJ, Belani A, Kramer BS, et al.: Impact of air filtration on nosocomial Aspergillus infections. Unique risk of bone marrow transplant recipients. Am J Med 83 (4): 709-18, 1987.
17. Schiffer CA: Granulocyte transfusions: an overlooked therapeutic modality. Transfus Med Rev 4 (1): 2-7, 1990.
18. Wade JC, Schimpff SC, Hargadon MT, et al.: A comparison of trimethoprim-sulfamethoxazole plus nystatin with gentamicin plus nystatin in the prevention of infections in acute leukemia. N Engl J Med 304 (18): 1057-62, 1981.
19. Scherrer R, Geissler K, Kyrle PA, et al.: Granulocyte colony-stimulating factor (G-CSF) as an adjunct to induction chemotherapy of adult acute lymphoblastic leukemia (ALL). Ann Hematol 66 (6): 283-9, 1993.
20. Larson RA, Dodge RK, Linker CA, et al.: A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood 92 (5): 1556-64, 1998.

Adult Acute Lymphoblastic Leukemia in Remission

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 chemoradiation therapy with allogeneic stem cell rescue (alloBMT), and high-dose therapy with autologous stem cell rescue (autoBMT). Several trials, including a Cancer and Leukemia Group B study (CLB-8811), 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 two 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] Imatinib has been incorporated into maintenance regimens in patients with Ph1-postive ALL.[8,9,10]

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.[11]

The results of a series of retrospective and prospective studies published between 1987 and 1994 suggest that alloBMT or autoBMT as postremission therapy offer no survival advantage over intensive chemotherapy, except perhaps for patients with high risk or Ph1 positive ALL.[12,13,14,15] The use of alloBMT as primary postremission therapy is limited by both the need for an HLA-matched sibling donor and the increased mortality from alloBMT in patients in their fifth or sixth decades. The mortality from alloBMT using an HLA-matched sibling donor in these studies ranged from 20% to 40%.

Following on the results of these earlier studies, the International ALL Trial (ECOG-2993) was launched as an attempt to examine the role of transplant as postremission therapy for ALL more definitively and accrued patients from 1993 to 2006.[16] Patients with Ph1 negative ALL between the ages of 15 to 59 received identical multiagent induction therapy resembling previously published regimens.[1,2,3] Patients in remission were then eligible for HLA typing; patients with a fully matched sibling donor underwent alloBMT as consolidation. Those patients lacking a donor were randomly assigned to receive either an autoBMT or maintenance chemotherapy. The primary outcome measured was overall survival (OS), with event-free survival, relapse rate, and nonrelapse mortality as secondary endpoints. A total of 1,929 patients were registered and stratified according to age, white blood cell count, and time-to-remission. High-risk patients were defined as those having a high white blood cell count at presentation or those older than age 35. Ninety percent of patients in this study achieved remission after induction therapy. Of these patients, 443 were found to have an HLA-identical sibling, 310 of whom underwent alloBMT. For the 456 patients in remission who were eligible for transplant but lacked a donor, 227 received chemotherapy alone, while 229 underwent an autoBMT. By donor-to-no-donor analysis, standard risk ALL patients with an HLA-identical sibling had a 5-year OS of 53% compared with 45% for patients lacking a donor (P = .01). In subgroup analysis, the advantage for patients with donors remained significant for patients with standard risk ALL (OS = 62% vs. 52%; P = .02). For patients with high-risk disease (age older than 35 or high white blood cell count), the difference in OS was 41% versus 35% (donor vs. no donor), but was not significant (P = .2). Relapse rates were significantly lower (P < .00005) for both standard and high-risk patients with HLA-matched donors. In contrast to alloBMT, autoBMT was less effective than maintenance chemotherapy as postremission treatment (5-year OS = 46% for chemotherapy vs. 37% for autoBMT; P = .03). The results of this trial seem to confirm the existence of a graft versus leukemia effect for adult Ph1 negative ALL and support the use of sibling donor alloBMT as the consolidation therapy providing the greatest chance for long term survival for standard risk adult ALL in first remission.[16][Level of evidence: 2A] The results also suggest that in the absence of a sibling donor, maintenance chemotherapy is preferable to autoBMT as postremission therapy.[16][Level of evidence: 2A]

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 fifth or sixth 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 radiation therapy administered is associated with the incidence of acute and chronic GVHD and may be an independent predictor of leukemia-free survival.[17][Level of evidence: 3iiB]

Aggressive cyclophosphamide-based regimens similar to those used in aggressive non-Hodgkin lymphoma have shown improved outcome of prolonged disease-free status for patients with B-cell ALL (L3 morphology, surface immunoglobulin positive).[18] Retrospectively reviewing three 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 two 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 B-cell (Burkitt) lymphoma section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)

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.[19]

1. Cranial radiation therapy plus intrathecal (IT) methotrexate.
2. High-dose systemic methotrexate and IT methotrexate without cranial radiation therapy.
3. IT chemotherapy alone.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

General information about clinical trials is also available from the NCI Web site.

References:

1. Gaynor J, Chapman D, Little C, et al.: A cause-specific hazard rate analysis of prognostic factors among 199 adults with acute lymphoblastic leukemia: the Memorial Hospital experience since 1969. J Clin Oncol 6 (6): 1014-30, 1988.
2. Hoelzer D, Thiel E, Löffler H, et al.: Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71 (1): 123-31, 1988.
3. Linker CA, Levitt LJ, O'Donnell M, et al.: Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood 78 (11): 2814-22, 1991.
4. Zhang MJ, Hoelzer D, Horowitz MM, et al.: Long-term follow-up of adults with acute lymphoblastic leukemia in first remission treated with chemotherapy or bone marrow transplantation. The Acute Lymphoblastic Leukemia Working Committee. Ann Intern Med 123 (6): 428-31, 1995.
5. Larson RA, Dodge RK, Burns CP, et al.: A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 85 (8): 2025-37, 1995.
6. Cuttner J, Mick R, Budman DR, et al.: Phase III trial of brief intensive treatment of adult acute lymphocytic leukemia comparing daunorubicin and mitoxantrone: a CALGB Study. Leukemia 5 (5): 425-31, 1991.
7. Dekker AW, van't Veer MB, Sizoo W, et al.: Intensive postremission chemotherapy without maintenance therapy in adults with acute lymphoblastic leukemia. Dutch Hemato-Oncology Research Group. J Clin Oncol 15 (2): 476-82, 1997.
8. Thomas DA, Faderl S, Cortes J, et al.: Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 103 (12): 4396-407, 2004.
9. Yanada M, Takeuchi J, Sugiura I, et al.: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 24 (3): 460-6, 2006.
10. Wassmann B, Pfeifer H, Goekbuget N, et al.: Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 108 (5): 1469-77, 2006.
11. Finiewicz KJ, Larson RA: Dose-intensive therapy for adult acute lymphoblastic leukemia. Semin Oncol 26 (1): 6-20, 1999.
12. Horowitz MM, Messerer D, Hoelzer D, et al.: Chemotherapy compared with bone marrow transplantation for adults with acute lymphoblastic leukemia in first remission. Ann Intern Med 115 (1): 13-8, 1991.
13. Sebban C, Lepage E, Vernant JP, et al.: Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. French Group of Therapy of Adult Acute Lymphoblastic Leukemia. J Clin Oncol 12 (12): 2580-7, 1994.
14. Forman SJ, O'Donnell MR, Nademanee AP, et al.: Bone marrow transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 70 (2): 587-8, 1987.
15. Fière D, Lepage E, Sebban C, et al.: Adult acute lymphoblastic leukemia: a multicentric randomized trial testing bone marrow transplantation as postremission therapy. The French Group on Therapy for Adult Acute Lymphoblastic Leukemia. J Clin Oncol 11 (10): 1990-2001, 1993.
16. Goldstone AH, Richards SM, Lazarus HM, et al.: In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 111 (4): 1827-33, 2008.
17. Corvò R, Paoli G, Barra S, et al.: Total body irradiation correlates with chronic graft versus host disease and affects prognosis of patients with acute lymphoblastic leukemia receiving an HLA identical allogeneic bone marrow transplant. Int J Radiat Oncol Biol Phys 43 (3): 497-503, 1999.
18. Hoelzer D, Ludwig WD, Thiel E, et al.: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87 (2): 495-508, 1996.
19. Kantarjian HM, Walters RS, Smith TL, et al.: Identification of risk groups for development of central nervous system leukemia in adults with acute lymphocytic leukemia. Blood 72 (5): 1784-9, 1988.

Recurrent Adult Acute Lymphoblastic Leukemia

Patients with acute lymphoblastic leukemia (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 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]

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 mutants, 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 leuekmia, one of which included small numbers of patients with lymphoid blast crisis or Ph1-positive ALL. In one study, 10 such patients were treated with dasatinib in a dose escalation study.[9] Seven of these patients had a complete hematologic response (<5% marrow blasts with normal peripheral blood counts), three of whom had a complete cytogenetic response. The common toxicities were reversible myelosuppression (89%) and pleural effusions (21%). Virtually all of these patients relapsed within 6 months of the start of treatment with dasatinib.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

General information about clinical trials is also available from the NCI Web site.

References:

1. Herzig RH, Bortin MM, Barrett AJ, et al.: Bone-marrow transplantation in high-risk acute lymphoblastic leukaemia in first and second remission. Lancet 1 (8536): 786-9, 1987.
2. Thomas ED, Sanders JE, Flournoy N, et al.: Marrow transplantation for patients with acute lymphoblastic leukemia: a long-term follow-up. Blood 62 (5): 1139-41, 1983.
3. Barrett AJ, Horowitz MM, Gale RP, et al.: Marrow transplantation for acute lymphoblastic leukemia: factors affecting relapse and survival. Blood 74 (2): 862-71, 1989.
4. Dinsmore R, Kirkpatrick D, Flomenberg N, et al.: Allogeneic bone marrow transplantation for patients with acute lymphoblastic leukemia. Blood 62 (2): 381-8, 1983.
5. Sallan SE, Niemeyer CM, Billett AL, et al.: Autologous bone marrow transplantation for acute lymphoblastic leukemia. J Clin Oncol 7 (11): 1594-601, 1989.
6. Paciucci PA, Keaveney C, Cuttner J, et al.: Mitoxantrone, vincristine, and prednisone in adults with relapsed or primarily refractory acute lymphocytic leukemia and terminal deoxynucleotidyl transferase positive blastic phase chronic myelocytic leukemia. Cancer Res 47 (19): 5234-7, 1987.
7. Biggs JC, Horowitz MM, Gale RP, et al.: Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy. Blood 80 (4): 1090-3, 1992.
8. Gray JR, Wallner KE: Reversal of cranial nerve dysfunction with radiation therapy in adults with lymphoma and leukemia. Int J Radiat Oncol Biol Phys 19 (2): 439-44, 1990.
9. Talpaz M, Shah NP, Kantarjian H, et al.: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354 (24): 2531-41, 2006.

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Changes to This Summary (09 / 10 / 2009)

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.

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ABOUT PDQ

  • PDQ® - NCI's Comprehensive Cancer Database.
    Full description of the NCI PDQ database.

ADDITIONAL PDQ SUMMARIES

  • PDQ® Cancer Information Summaries: Adult Treatment
    Treatment options for adult cancers.
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    Treatment options for childhood cancers.
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    Tests or procedures that detect specific types of cancer.
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    Risk factors and methods to increase chances of preventing specific types of cancer.
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    Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.
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    Information about complementary and alternative forms of treatment for patients with cancer.

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Date Last Modified: 2009-09-10

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