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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. [4,5,6,7,8,9,10]
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 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.