Capizzi-Style Methotrexate with Pegasparagase (C-MTX) Is Superior to High-Dose Methotrexate (HDMTX) in T-Lineage Acute Lymphoblastic Leukemia (T-ALL): Results from Children's Oncology Group (COG) AALL0434
Authors: Winter Stuart S. , Devidas Meenakshi , Chen Si , Asselin Barbara , Carroll William L. , Wood Brent L , Esiashvili Natia , Nikki Briegel J , Hayashi Robert J. , Loh Mignon L. , Carroll Andrew J. , Heerema Nyla A. , Raetz Elizabeth , Winick Naomi J. , Hunger Stephen P. , Dunsmore Kimberly P. 
Published: October 2019

Abstract

Early intensification with MTX is a key component of most treatment regimens used for children, adolescents and young adults with ALL. We have previously shown that HDMTX is superior to C-MTX in B-ALL in COG Study AALL0232. Because there are differences in sensitivity to MTX and pegaspargase (PEG-ASNase) between B- and T-ALL that might affect outcome, we conducted a front-line, Phase III study for patients with T-ALL. COG AALL0434 was a 2 x 2 pseudo-factorial randomization comparing the COG augmented BFM (ABFM) regimen with C-MTX without leucovorin rescue to ABFM with HDMTX plus leucovorin rescue in T-ALL, and randomizing patients with T-ALL and T-lymphoblastic lymphoma to therapy with/without six, five-day courses of nelarabine. Study subjects with T-ALL received either block of MTX therapy during the 8-week Interim Maintenance (IM) phase; those with CNS3 status were non-randomly assigned to receive HDMTX. The T-ALL patients all received prophylactic (1200 cGy) or therapeutic (1800 cGy for CNS3) cranial irradiation (cXRT), except for the ~10% with low-risk T-ALL (NCI standard risk, CNS1 without extramedullary disease, and Day 29 minimal residual disease <0.1%), who did not receive cXRT. AALL0434 accrued 1,895 study subjects between 2007 and 2014. One thousand thirty-one T-ALL subjects without CNS3 status were randomized to receive ABFM with C-MTX or HDMTX. Subjects randomized to C-MTX (n= 518) received cXRT during Consolidation (Week 4 of protocol therapy), while subjects randomized to HDMTX (n=513) received cXRT during Delayed Intensification (DI) Week 26 of protocol therapy. The 4-year disease-free survival rates (DFS) were 89.3% (SE 1.5%) overall and 92.5% (SE 1.8%) for the C-MTX regimen vs. 86.1% (SE 2.4%) for the HDMTX regimen (p = 0.0173) (Figure 1). Interim monitoring resulted in the early release of efficacy results showing that C-MTX is superior to HDMTX, but data for the nelarabine randomization (n = 659) have not yet matured enough to assess its impact. The C-MTX regimen had 11 relapses; 7 without CNS, and 4 with CNS involvement, all occurring after Week 21 in DI phase therapy. In contrast, among those randomized to HDMTX, there were 24 relapses, 14 without CNS and 10 with CNS involvement, 6 with CNS before delivery of HDMTX and cXRT. This result is directly opposite to what we observed in B-ALL (Larsen et al, ASCO 2011), emphasizing the different biology and treatment sensitivities of B- and T-ALL. The reasons for these differences are uncertain, but may be related to different sensitivities to MTX with/without leucovorin rescue, differences in PEG-ASNase scheduling, or near universal use of cXRT in AALL0434 with different timings of cXRT administration between study arms. In conclusion, AALL0434 produced a 4-year DFS rate of 89.3% (SE 1.5%) in children, adolescents, and young adults with T-ALL, and established that ABFM with C-MTX was superior to ABFM plus HDMTX.
Figure 1. Figure 1.

Disclosures
Hunger: Bristol-Myers Squibb: Employment; Jazz Pharmaceuticals; Sigma Tau Pharmaceuticals; Erytech: Honoraria.