Delayed Intensification (DI) Enhances Event-Free Survival (EFS) of Children with B-Precursor Acute Lymphoblastic Leukemia (ALL) Who Received Intensification Therapy with Six Courses of Intravenous Methotrexate (MTX): POG 9904/9905: A Childrens Oncology Group Study (COG).
Authors: Winick Naomi , Martin Paul L. , Devidas Meenakshi , Shuster Jonathan , Borowitz Michael J. , Bowman Paul , Larsen Eric , Pullen Jeanette , Hunger Stephen P. , Carroll William L. , Camitta Bruce M. 
Published: October 2019

Abstract
Post-induction (ind) intensification with non-anti-metabolite based blocks of therapy, improved EFS on BFM 76/79, CCG 105 and UKALL X. The DI phase of reinduction-reconsolidation (BFM protocol II) was a major component of these strategies. An anti-metabolite based (MTX/mercaptopurine [MP]) intensification also improved EFS (POG 9005/9006). COG 9904 and 9905 addressed whether addition of DI improved EFS for a subset of lower, standard (std) and a subset of NCI high risk (HR) pts who all received 6 courses (cs) of IV MTX (1 gm/m2/24 hrs vs 2 gm/m2/4 hrs) plus oral MP as intensification. The results of the MTX randomization (4 vs 24 hrs) are still blinded. Ind was a dexamethasone (dex)-based 3-drug (NCI std risk) or prednisone-based 4-drug (NCI HR or std with extramedullary disease) regimen. The 3-drug ind was modified because of excessive mortality with the intrathecal (IT) MTX on day 1 changed to IT Ara-C and 6 doses of native asparaginase (asp) (10,000 IU/m2) replaced with 1 dose of PEG asp. 1124 pts were treated pre-; 477 post-amendment. Post-ind, NCI std risk pts with trisomies of chromosomes 4 and 10 or a TELAML1 (TEL) translocation were classified as lower risk and enrolled on 9904. Only the TEL pts participated in the DI randomization. Std risk pts without and HR pts with favorable blast cytogenetics, or pts who did not meet refined NCI high risk age and WBC criteria were eligible for 9905. Pts with CNS3 disease, t(9;22), t(4;11), or hypodiploidy were excluded from both studies. Consolidation on 9904/9905 included 6 cs of IV MTX with leucovorin rescue for all pts. DI began at wk 16 after the 3rd course of IV MTX and was delivered over 8 wks: 1.5 mg/m2 vincristine and 30 mg/m2 daunomycin (wks 1, 2 and 3), daily dex (6 mg/m2 × 21 days), 2500 IU/m2 PEG asp (wk 1), age adjusted IT MTX (wks 1, 5, 6), 75 mg/m2 Ara-C (IV /SC) daily × 4 days (wks 5 and 6), 1 gm/m2 cyclophosphamide (wk 5) and 60 mg/m2 6-thioguanine daily × 14 doses (wks 6–7). A total of 1403 patients were randomized to +/− DI between April 7, 2000 and April 15, 2005. There were only 2 remission deaths; 1 each in +/− DI arms. There was a statistically significant improvement in EFS for all pts receiving the DI, with no statistically significant interaction (size of treatment differences in 4 yr EFS) between any pair of subsets. The difference, though not significant (study not powered to look at subsets), for the 9905 NCI HR pts with and without favorable cytogenetics, was in the same direction as the overall results, but still suboptimal with EFS below 80%. This may reflect differences between the dex and anthracycline used during the DI phase in this study versus BFM 76/69 and CCG 105 and/or the need for an intervention other than this DI in NCI HR patients.
No DI DI Cohort 4 yr EFS N 4 yr EFS N 1 sided p-value* *p-values are by the logrank test Overall (9904/9905 NCI Std & High Risk) 81.6±2.0% 710 86.5±1.7% 693 0.0049 9904/9905 NCI Standard Risk 84.5±2.1% 517 90.3±1.7% 512 0.0012 9904 NCI Std Risk with TELAML1 91.1±2.6% 217 93.6±2.2% 216 0.0900 9905 NCI Std Risk 79.8±3.2% 300 87.9±2.5% 296 0.0027 9905 NCI HR 74.3±4.3% 93 76.2±4.5% 181 0.3839