The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95.
In the Non-Hodgkin Lymphoma-Berlin-Frankfurt-Münster 95 (NHL-BFM95) study, we tested by randomization whether for patients with B-cell neoplasms methotrexate as intravenous infusion over 4 hours (MTX-4h) is not inferior to, but less toxic than, a 24-hour intravenous infusion (MTX-24h). Second, we investigated against the historical control of study NHL-BFM90, whether for patients with moderate tumor mass MTX can be reduced from 5 g/m(2) to 1 g/m(2). Patients received 2 5-day therapy courses in risk group R1 (resected), 4 in R2 (lactate dehydrogenase [LDH] < 500 U/L), 5 in R3 (LDH > 500 to < 1000 U/L) and 6 in R4 (LDH > 1000 U/L and/or central nervous system [CNS] disease). Courses contained MTX 1 g/m(2) in R1 + R2 and 5 g/m(2) in R3 + R4. Of 505 patients (April 1996 to March 2001), 364 were randomized to receive MTX-4h or MTX-24h. Failure-free survival (pFFS, 1 year) for arm MTX-4h versus MTX-24h, respectively, was 95% +/- 5% (n = 20) versus 100% (n = 19) in R1, 94% +/- 2% (n = 88) versus 96% +/- 2% (n = 95) in R2, and 77% +/- 5% (n = 62) versus 93% +/- 3% (n = 69) in R3 +/- R4 (per-protocol analysis). Incidence of mucositis grade III/IV was significantly lower with MTX-4h in all risk groups. For patients in R2, event-free survival (pEFS) was 95% +/- 2% (n = 222) in NHL-BFM95 (MTX 1 g/m(2)) and 97% +/- 1% (n = 154) in NHL-BFM90 (MTX 5 g/m(2)). In conclusion, MTX-4h was less toxic than MTX-24h. MTX-4h was noninferior to MTX-24h for limited stage B-cell non-Hodgkin lymphoma (B-NHL) but not for advanced disease. For limited disease, MTX 1 g/m(2) is noninferior to 5 g/m(2).
Department of Pediatric Hematology and Oncology, Justus-Liebig-University, D-35385 Giessen, Germany.
Wilhelm
W
Woessmann
Kathrin
K
Seidemann
Georg
G
Mann
Martin
M
Zimmermann
Birgit
B
Burkhardt
Ilske
I
Oschlies
Wolf-Dieter
WD
Ludwig
Thomas
T
Klingebiel
Norbert
N
Graf
Bernd
B
Gruhn
Heribert
H
Juergens
Felix
F
Niggli
Reza
R
Parwaresch
Helmut
H
Gadner
Hansjoerg
H
Riehm
Martin
M
Schrappe
Alfred
A
Reiter
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000627:therapeutic use*; D016019:Survival Analysis; D013997:Time Factors
D008727:Methotrexate