High-dose Methotrexate Improves Outcome in High-risk B-cell Precursor Acute Lymphoblastic Leukemia
Slow early responders gain most benefi t from high dose compared with Capizzi methotrexate
In children and young adults with high-risk acute lymphoblastic leukemia (ALL), high-dose methotrexate is more effective than escalating Capizzi methotrexate plus asparaginase in interim maintenance-1 therapy, suggest results of a randomized, phase III trial presented by Eric C. Larsen, MD, of Maine Children’s Cancer Program.
| "The improvement in outcomes achieved with high-dose methotrexate resulted from the optimization of chemotherapy that has been in use for 50 years." |
 |
|
— Eric C. Larsen, MD
|
The AALL0232 trial (Abstract 3), which enrolled 3,154 patients with newly diagnosed high-risk B-cell precursor ALL between January 2004 and January 2011, was halted after high-dose methotrexate demonstrated a significant improvement in 5-year event-free survival (EFS) compared with Capizzi methotrexate regimens (82.0% vs. 75.4%; p = 0.006).
High-dose methotrexate was also well tolerated, in fact demonstrating less toxicity than escalating Capizzi methotrexate. Based on these results, Discussant Martin S. Tallman, MD, of Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, called high-dose methotrexate "the new standard of care for high-risk ALL."
Methotrexate first demonstrated efficacy more than 50 years ago and has since become the cornerstone of maintenance therapy. Although both high-dose and Capizzi methotrexate have demonstrated efficacy, the two approaches had not been directly compared. The AALL0232 trial was developed to compare two different strategies for enhancing central nervous system (CNS) control, given the relative increase in CNS failures that has been occurring.
The trial was open to individuals aged 30 or younger with newly diagnosed B-cell precursor ALL meeting the National Cancer Institute high-risk criteria, which include all patients aged 10 or younger with a white blood cell count of at least 50,000 cells/μL.
The study used a 2x2 factorial design, in which patients were randomly assigned to receive prednisone or dexamethasone in induction therapy, followed by consolidation for 8 weeks. Patients were then randomly assigned to receive high-dose methotrexate or Capizzi methotrexate as interim maintenance-1 therapy.
Patients in the high-dose methotrexate arm (1,209 patients) received 5 gm/m2 of methotrexate on days 1, 15, 29, and 43, leucovorin rescue, 6-mercaptopurine, intrathecal methotrexate, and vincristine. Patients in the Capizzi methotrexate arm (1,217 patients) received escalating methotrexate on days 1, 11, 21, 31, and 41 (with no leucovorin rescue), pegylated asparaginase, intrathecal methotrexate, and vincristine.
All patients received the same delayed intensification treatment, and subsequent treatment was dependent on the speed of response to induction therapy. Rapid early responders (M1 by day 15 and minimal residual disease [MRD] < 0.1% on day 29) received one interim maintenance/delayed intensification (IM/DI); slow early responders (≥ M2 on day 15 or MRD ≥ 0.1% on day 29) received two IM/DI. Cranial radiation was used in patients with CNS disease and in slow early responders during delayed intensification-2.
During the follow-up period, 142 treatment failures were reported in the high-dose methotrexate arm, and 190 treatment failures were reported in the Capizzi methotrexate arm. The most common causes of treatment failure included induction failure (46 patients receiving high-dose methotrexate and 54 patients receiving Capizzi methotrexate), marrow relapse (42 and 68 patients, respectively), and isolated CNS relapse (22 and 32 patients, respectively).
Key toxicities at least grade 3 in severity included functional mucositis (8.4% of patients receiving high-dose methotrexate vs. 7.6% of patients receiving Capizzi methotrexate), mucositis determined by exam (7.2% vs. 8.3%), and febrile neutropenia, which occurred at a significantly lower rate with high-dose methotrexate than with Capizzi methotrexate (5.2% vs. 8.2%; p = 0.005).
Patients with slow early responses to therapy appear to gain the most benefit from high-dose methotrexate. Among the 435 patients with slow early responses, the 5-year EFS rate was 79.5% with high-dose methotrexate and 65.4% with Capizzi methotrexate (p = 0.04). Conversely, in the 1,843 patients with rapid early responses, 5-year EFS rates were 86.6% and 82.7%, respectively (p = 0.09).
Dr. Larsen noted that the improvement in outcomes achieved with high-dose methotrexate resulted from the optimization of chemotherapy that has been in use for 50 years. He suggested that additional progress in the treatment of ALL will likely result from therapies aimed at molecular targets.