Treatment for Untreated Adult ALL
Standard Treatment Options for Untreated Adult ALL
Standard treatment options for untreated adult acute lymphoblastic leukemia (ALL) include the following:
Remission induction therapy, including the following:
- Combination chemotherapy.
- Imatinib mesylate (for patients with Philadelphia chromosome [Ph1]-positive ALL).
- Imatinib mesylate combined with combination chemotherapy (for patients with Ph1-positive ALL)
- Supportive care.
Central nervous system (CNS) prophylaxis therapy, including the following:
- Cranial radiation therapy plus intrathecal (IT) methotrexate.
- High-dose systemic methotrexate and IT methotrexate without cranial radiation therapy.
- IT chemotherapy alone.
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. [4-10]
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.[15-17] At the present time, no conclusions can be drawn regarding the optimal imatinib dose or schedule.
- In a study of imatinib combined with chemotherapy from the Northern Italy Leukemia Group, patients with newly diagnosed, untreated Ph1-positive ALL were treated with an induction regimen containing idarubicin, vincristine, prednisone, and L-asparaginase. After accrual of an initial cohort, the study was modified to include the use of imatinib (600 mg per day from days 15 to 21). In consolidation, patients received imatinib (600 mg per day for 7 days) beginning 3 days prior to the start of each course of chemotherapy.
- For all patients who achieved remission, the intent was to proceed to allogeneic transplant when and if an HLA-matched donor could be identified. Patients lacking a donor received an autologous transplant. After completion of chemotherapy and transplant, all patients were to receive maintenance imatinib for as long as tolerated. After 20 patients had accrued to the imatinib arm, L-asparaginase was omitted from the induction regimen from both arms because of toxicity.
- Outcomes for the first cohort of 35 patients (imatinib-free) were compared to those of the subsequent cohort of 59 (imatinib-treated) patients. For patients treated with imatinib, OS probability was 38% at 5 years (median, 3.1 years) versus 23% in the imatinib-free group (median, 1.1 years; P = .009).[Level of evidence: 3iii]
- The drawbacks of this nonrandomized study are the small sample size (94 total patients) and the change in the treatment regimen (omission of L-asparaginase) midway through the study. However, the results suggest that inclusion of imatinib into a relatively standard chemotherapy regimen for newly diagnosed adult patients with Ph1-positive ALL may provide a significant survival advantage.
- In another study, ten patients with Ph1-positive ALL and ten patients with chronic myelogenous leukemia in lymphoid blast crisis were treated with doses of imatinib ranging from 300 mg to 1,000 mg per day. Of these 20 patients, four had complete hematologic remission and ten 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. The overall response rate was 60%, with 9 out of 48 patients (19%) achieving a CR. The responses again were short, with a median duration of 2.2 months.
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.
Evidence (Supportive care):
- Randomized clinical trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000/mm3 rather than at a level of 20,000/mm3.
- The incidence of platelet alloimmunization was
similar among groups randomly assigned to receive one of the following from random donors:
- Pooled platelet concentrates.
- Filtered, pooled platelet concentrates.
- Ultraviolet B-irradiated, pooled platelet concentrates.
- Filtered platelets obtained by apheresis.
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.
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).[31-33] 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.
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Dinsmore R, Kirkpatrick D, Flomenberg N, et al.: Allogeneic bone marrow transplantation for patients with acute lymphoblastic leukemia. Blood 62 (2): 381-8, 1983. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Kantarjian H, Thomas D, O'Brien S, et al.: Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer 101 (12): 2788-801, 2004. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Bassan R, Rossi G, Pogliani EM, et al.: Chemotherapy-phased imatinib pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: Northern Italy Leukemia Group protocol 09/00. J Clin Oncol 28 (22): 3644-52, 2010. [PUBMED Abstract]
- Slichter SJ: Controversies in platelet transfusion therapy. Annu Rev Med 31: 509-40, 1980. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Rubin M, Hathorn JW, Pizzo PA: Controversies in the management of febrile neutropenic cancer patients. Cancer Invest 6 (2): 167-84, 1988. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Schiffer CA: Granulocyte transfusions: an overlooked therapeutic modality. Transfus Med Rev 4 (1): 2-7, 1990. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Hoelzer D, Ludwig WD, Thiel E, et al.: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87 (2): 495-508, 1996. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Thomas DA, Cortes J, O'Brien S, et al.: Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol 17 (8): 2461-70, 1999. [PUBMED Abstract]