Improved Early Event Free Survival (EFS) in Children with Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) with Intensive Imatinib in Combination with High Dose Chemotherapy: Children’s Oncology Group (COG) Study AALL0031.
Authors: Schultz Kirk R. , Bowman W. Paul , Slayton William , Aledo Alex , Devidas Meenakshi , Sather Harland , Borowitz Michael J. , Davies Stella M. , Trigg Michael , Pasut Bernice , Jorstad Dean , Eslinger Tammie , Burden Laura E. , Wang Chenguang , Rutledge Robert , Gaynon Paul S. , Carroll Andrew J. , Heerema Nyla A. , Winick Naomi , Hunger Stephen , Carroll William L. , Camitta Bruce 
Published: October 2019

Abstract
Ph+ ALL remains one of the highest risk subsets of childhood ALL. The COG AALL0031 protocol (open 2002 – 2006) gave imatinib at 340 mg/m2 for an increasing number of days in combination with an intensive chemotherapy backbone. Cohorts received 42 days of imatinib exposure (Cohort 1 N= 8), 63 days (Cohort 2 N=12), 84 days (Cohort 3 N=11), 126 days (Cohort 4 N=12) and 280 continuous days (Cohort 5 N=50) prior to maintenance therapy. If an HLA-identical sibling donor was available, a BMT was performed after the first two cycles of therapy post induction otherwise chemotherapy was continued. BMT patients received imatinib starting 4 – 6 months post BMT for a 6 month duration. Ninety-three patients were treated, 10 of whom had failed induction (induction failures were removed from the following analyses). We observed that MRD positivity (<0.01%) was significantly lower (p = 0.0002) after consolidation block 1 and after consolidation block 2 (p = 0.007) in Cohorts 3 – 5 (imatinib in consolidation blocks 1& 2) versus Cohorts 1/2 combined (no imatinib in consolidation blocks 1&2). Early EFS improved with increasing imatinib exposure with a 1 year EFS of 70.6±11.1% for Cohorts 1 & 2, 90.9±6.4% for Cohorts 3&4, and 95.3±3.6% for Cohort 5 (p = 0.02). The 1 year EFS for Cohort 5 was significantly higher than for historical controls from previous COG studies (N=56; 1 year EFS 65.7±6,4%; p = 0.006). Twenty-one patients had matched sibling transplants (8 of 43 in Cohorts 1 – 4 and 13 of 44 in Cohort 5). Eleven of 83 (13%) patients were removed from protocol by treating institutions for alternative donor BMT. Intent-to-treat analysis does not show a statistically significant difference in early outcome between those patients in Cohort 5 treated without sibling donor BMT compared to patients who received a matched sibling donor BMT (p = 0.26). The related donor BMT group treated with 6 months of Imatinib post BMT had a higher 1 year EFS compared to a comparable historical BMT group receiving no Imatinib on prior pediatric cooperative group protocol with a 1 year EFS 78%. Cohort 5 chemotherapy treatment group outcomes were not significantly affected after removal of patients receiving off protocol BMT. We conclude that imatinib given in combination with intensive chemotherapy resulted in a significant improvement in early EFS and reduction in early MRD. Post BMT imatinib also improved early outcome in related donor BMT. Intensive imatinib with intensive chemotherapy gives equivalent early EFS to patients treated with allogeniec related or alternative donor BMT. Longer observation will be required to see if this results in a difference in long term EFS.
Outcome in patients on COG protocol, AALL0031 Therapy given N 1 year EFS SE Intent-to-treat analysis - Cohort 5 Chemotherapy with continuous dosing imatinib (includes 6 patients removed from study for alternative donor BMT) 31 96.7% 3.5% Intent-to-treat analysis - Sibling BMT (all Cohorts) 21 95.0% 5.3% Cohort 5 (with removal of alternative donor BMT patients) 25 95.8% 4.3% Off protocol alternative donor BMT (all cohorts) 11 81.8% 12.3%