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Capizzi-style methotrexate improves survival in pediatric T-cell acute lymphoblastic leukemia
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Capizzi-style methotrexate without leucovorin rescue induced superior outcomes compared with high-dose methotrexate with leucovorin rescue among children with T-cell acute lymphoblastic leukemia, according to study results from the Children’s Oncology Group AALL0434 trial.
ALL therapy often includes early intensification with methotrexate. Two different approaches exist for methotrexate intensification — Capizzi-style escalating IV methotrexate without leucovorin rescue plus pegaspargase Capizzi-style, IV methotrexate (C-MTX), and high-dose IV methotrexate plus leucovorin rescue (HDMTX) — but they have not been compared for T-cell ALL.
Studies have shown HDMTX to be superior to C-MTX for the treatment of B-cell ALL among high-risk children and adolescents.
But, because disease sensitivity to methotrexate and pegaspargase differ between B-ALL and T-ALL, Stuart S. Winter, MD, physician at Children’s Minnesota Cancer and Blood Disorders Program, and colleagues sought to compare C-MTX and HDMTX among 1,562 patients with T-ALL.
Investigators used a 2 x 2 randomization to compare a Children’s Oncology Group-augmented Berlin-Frankfurt-Muenster regimen (ABFM) with either C-MTX or HDMTX during an 8-week interim maintenance phase. In the second randomization, researchers analyzed the addition of six 5-day cycles of nelarabine (Arranon, Novartis), which will be reported on separately.
All patients, except for those with low-risk features, received 12 Gy prophylactic or 18 Gy (for CNS3 disease) therapeutic cranial irradiation with C-MTX in the second month of therapy or HDMTX in the seventh month of therapy.
Overall, results showed a 5-year EFS rate of 83.8% (95% CI, 81.2-86.4) and 5-year OS rate of 89.5% (95% CI, 87.4-91.7).
Of 1,189 patients eligible for postinduction randomization, 9.2% were deemed low risk, 68% intermediate risk and 19.2% high risk; 3.6% had induction failure.
A total of 1,031 patients with T-ALL but without CNS3 disease or testicular leukemia received ABFM with C-MTX (n = 519) or HDMTX (n = 512).
Patients who received C-MTX showed higher rates of 5-year DFS (91.5% vs. 85.3%; P = .005) and 5-year OS (93.7% vs. 89.4%; P = .04) than patients who received HDMTX.
Thirty-two patients who received C-MTX relapsed, six of whom had CNS involvement, compared with 59 relapses, 23 with CNS involvement, among patients who received HDMTX.
“Data from previous Children’s Oncology Group studies have shown that NCI risk status, recurring cytogenetic features, and other traditional prognostic factors in B-ALL have limited value in T-ALL, but results from the I-BFM-SG MRD and AEIOPBFM-2000 studies have shown that end-induction and end-consolidation minimal residual disease levels could portend risk for relapse,” the researchers wrote. “Although cytogenetic and phenotypic findings in T-ALL have not been useful for treatment assignment, these and other biomarkers, in combination with minimal residual disease, may better risk stratify high-risk disease, as demonstrated in the FRALLE2000T study. The improved survival rates observed for COG AALL0434 may better position us to include biomarkers with minimal residual disease to further improve survival in future trials.” – by Melinda Stevens
Disclosures: Winter reports stock or other ownership with Amgen and a consultant/advisory role with Jazz Pharmaceuticals. Please see the study for all other authors’ relevant financial disclosures.
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