Intensive oral methotrexate protects against lymphoid marrow relapse in childhood B-precursor acute lymphoblastic leukemia.

Abstract

PURPOSE To describe the use of combination chemotherapy, including divided-dose oral methotrexate (dMTX), for children with B-precursor acute lymphoblastic leukemia (ALL). dMTX produced prolonged MTX exposure on an outpatient basis. PATIENTS AND METHODS Two hundred forty-three patients were treated from January 1986 to May 1992. dMTX was given weekly during consolidation and biweekly for the first 16 months of continuation therapy with mercaptopurine (6-MP) and asparaginase (L-ASP). Initially, etoposide (VP-16) and cytarabine (Ara-C) pulses were included. Treatment continued for 30 months with single-dose weekly MTX replacing dMTX during continuation, part 2. Unexpected acute neurotoxicity was eliminated by the addition of leucovorin. VP-16 and Ara-C were omitted in the face of acute myelogenous leukemia (AML). RESULTS Two hundred thirty-nine patients entered remission: 16 had a lymphoid marrow relapse, two each with testicular or CNS relapse; 19 a CNS relapse; 16 secondary AML; three other second malignancies; two withdrew for transplant; three died in remission; 16 withdrew because of noncompliance, and nine withdrew with toxicity. Event-free survival (EFS) at 4 years was 73 +/- 4%; 81 +/- 4% for 150 patients with better risk features and 60 +/- 7% for 93 with high-risk features. Lymphoid marrow relapse-free survival in the standard- and high-risk patients was 94 +/- 3% and 86% +/- 6%, respectively. The most common adverse event was secondary AML in the standard-risk group and isolated CNS relapse in the high-risk group. CONCLUSION This therapy produced an overall EFS similar to other published regimens, but the pattern of failures is very different, with few patients having a lymphoid marrow relapse. These data suggest that highly effective therapy for children with ALL can be delivered on an outpatient basis using a regimen featuring repetitive dMTX.

Phase II Trial of Oral Aminopterin for Adults and Children with Refractory Acute Leukemia

“…Mucosal toxicity was dose limiting at higher doses and ameliorated by dose reduction and/or the addition of leucovorin rescue. The observed toxicity at the maximum tolerated dose was similar to that observed in patients given methotrexate (25 mg/m 2 ) q6H for four doses weekly as a component of therapy for ALL (18).…”

“…Because the most accepted role for an antifolate is not as a single agent, but in the setting of multiagent, post-remission therapy, our goal in the clinical development of aminopterin has been predicated on finding a dose and schedule to mimic the divided-dose oral methotrexate that has been used in post-induction therapy for patients with ALL (18,19). The maximum tolerated dose of aminopterin on our phase I trial was 2 mg/m 2 /dose q12 hours for two doses weekly (15).…”

Long-term results of treatment studies for childhood acute lymphoblastic leukemia: Pediatric Oncology Group studies from 1986–1994

“…Using a different rescue regimen, repeated oral methotrexate has been used successfully for consolidation by the DallasFort Worth group. 18 A recently completed POG ALL study for standard risk is evaluating divided dose oral methotrexate for delayed intensification prior to maintenance.…”

A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial

“…33,34 Potential reasons for these neurotoxicities have been reviewed in a previous publication, 34 Overall outcome data from this clinical trial compare favorably with previous POG trials and those of other groups treating children for HR-ALL (62-75%). [9][10][11][12][13][14][15][16][17][18][19][20] Because risk group criteria differ among large cooperative groups treating childhood ALL, external comparisons are difficult and hazardous. However, 66% of the patients in this study would be considered high risk by the CTEP/NCI consensus risk group definition (age у10 years, or WBC у50 000) thus adding some validity to cross comparisons.…”

“…[9][10][11][12][13][14][15][16][17][18][19][20] Increased toxicity was also noted with the aggressive use of myelosuppressive agents. 9,13,14,16,18,[19][20][21][22] However, preliminary results from POG 8698 suggested that early intensification with the less toxic combination of intermediate-dose methotrexate (MTX) and mercaptopurine (MP) might be as effective as the more myelosuppressive combinations used in another POG pilot study (POG 8398) for HR-ALL. 13,17 In 1991, the POG opened a group-wide randomized phase III clinical trial (POG 9006) to treat children with HR-ALL.…”