Philadelphia Chromosome Negative (Ph-) Very High Risk (VHR) Acute Lymphoblastic Leukemia (ALL) in Children and Adolescents: The Impact of Intensified Chemotherapy on Early Event Free Survival (EFS) in Children’s Oncology Group (COG) Study AALL0031.
Authors: Schultz Kirk R. , Bowman William Paul , Slayton William , Aledo Alexander , Devidas Meenakshi , Sather Harland , Borowitz Michael J. , Davies Stella M. , Trigg Michael , Pasut Bernice , Jorstad Dean , Eslinger Tammie , Burden Laura , Wang Chenguang , Rutledge Robert , Camitta Bruce , Gaynon Paul S. , Carroll Andrew J. , Heerema Nyla A. , Winick Naomi , Hunger Stephen P. , Carroll William L. 
Published: October 2019

Abstract
Background: VHR patients eligible for COG AALL0031 had an expected 5-year EFS ≤ 40% and consisted of those with Ph+ ALL, severe hypodiploidy (<44 chromosomes), and induction failure (IF) with >25% blasts at the end of standard induction therapy. Patients with hypodiploidy and IF are the subject of this report. Ph+ patients were reported previously (Blood Schultz KR, et. al. Blood2006; 108:87a.).
Methods: Between 10/14/02 and 10/20/06, 63 evaluable patients (41 hypodiploidy and 22 IF) were enrolled in AALL0031 after completion of a 3- or 4-drug induction, and begun on an intensive chemotherapy regimen. Induction failure patients not entering complete remission (CR) after the first two chemotherapy cycles, ifosfamide and etoposide (cycle 1) and IV cyclophosphamide, IV etoposide) followed by high dose methotrexate and high dose cytarabine (cycle 2), were removed from study. Remission patients were assigned to 8 cycles of standard maintenance. All patients received triple intrathecal chemotherapy followed by cranial irradiation. An HLA-identical blood and marrow transplantation (BMT), by donor availability or to an intensive ~2.2 year chemotherapy regimen. The intensive chemotherapy regimen included a reinduction block (daunomycin, cyclophosphamide, vincristine, L-asparaginase, dexamethasone), intensification block [IV methotrexate (Mtx), etoposide, cyclophosphamide, high dose cytarabine, L-asparaginase], with each block repeated followed by 4 cycles of intensive maintenance (high dose Mtx, PO Mtx, IV vincristine, PO 6-MP). Unrelated donor BMT was not an option on AALL0031.
Results: Twenty-one of 22 (95%) IF patients achieved CR after two cycles of therapy. Of these, 12 continued chemotherapy, 2 underwent BMT, and 7 were taken off protocol for an unrelated donor BMT. At 2-years, the EFS for IF patients was chemotherapy (46±17%) or related/unrelated donor BMT (67±17%; p = 0.50). Twenty-eight hypodiploidy patients continued chemotherapy, 12 underwent related donor BMT and 1 was taken off protocol for an unrelated donor BMT. For hypodiploid patients, the 2 year EFS was 57±10% for those receiving chemotherapy compared to related/unrelated donor BMT (67±14%, p=0.74). These outcomes compared favorably with COG historical controls (n=16, 44±12%; p=0.30). We lack a COG historical control for a comparison with IF patients. We examined minimal residual disease (MRD) at the end of cycle 2 in patients undergoing related/unrelated BMT and those receiving chemotherapy. With MRD > 0.01% (n=9) and < 0.01% (n=6), 2-year EFS was 56±19% and 83±15% (p=0.27), respectively. Chemotherapy groups showed a 2 year EFS for > 0.01% of 57±22% (N = 7) compared to 53±12% for ≤ 0.01% (N=19; p =0.83).
Conclusions: The AALL0031 regimen attained a very high CR (95%) for IF patients. Small number severely limited statistical power. We found better outcomes for AALL0031 versus historical data, for allogeneic BMT versus chemotherapy, and MRD negativity versus positivity in BMT patients, although none were statistically significant. Future strategies focused on inducing lower MRD early in therapy may improve outcomes for both chemotherapy and BMT. International collaborations to allow for higher patient accrual should be considered.