JALSG Ph (-) B-ALL213 Study: Pediatric-Type Chemotherapy Improves Prognosis in Adult Ph-Negative Acute Lymphoblastic Leukemia Patients, Including Older Adults

Background A pediatric-type regimen with an increased dose of L-asparaginase (L-ASP) and steroids is effective in adult patients with acute lymphoblastic leukemia (ALL). However, it does not improve prognosis in patients older than 55 years due to intolerance caused by adverse events. Prednisolone responsiveness is a prognostic factor in pediatric ALL, but it is unclear whether it is also a prognostic factor in adult ALL. To address these issues, the Japan Adult Leukemia Study Group (JALSG) conducted the pediatric-type regimen Ph (-) B-ALL213 for patients aged 15-64 years who were newly diagnosed with Ph-negative ALL. This study was reviewed and approved by the institutional review board of each participating institution. Methods Ph (-) B-ALL213 was a single-arm, multicenter phase II study (UMIN000010619). This regimen was based on our previous regimen, ALL202-O, which used high-dose methotrexate (HD-MTX). The main modifications from ALL202-O were the introduction of a prednisolone (PSL) prephase treatment before induction and an increased dose of L-ASP. After 7-days of PSL prephase treatment, the response to PSL was evaluated. PSL good responders (PGR) and PSL poor responders (PPR) were defined as having blasts < 1.0 x109/L and ≥ 1.0 x109/L at day 8, respectively. During induction, L-ASP 5,000 U/m2 was administered for 8 days. Consolidation 1 (C1) included a high-dose Ara-C phase with a single dose of L-ASP 10,000 U/m2. C2 was the HD-MTX phase, during which L-ASP 10,000 U/m2 was administered twice after HD-MTX. C3 was an intensive phase with 6 days of L-ASP 5,000 U/m2. C4 was same as C1 and C5 was same as C2. The total L-ASP dose was 130,000 U/m2. However, the L-ASP dose was reduced by half for patients aged 60-64 years. Maintenance therapy was continued for 2 years after the initiation of chemotherapy. All patients provided written informed consent prior to registration. Results Initially, 228 patients with ALL were enrolled between August 2013 and October 2016. After excluding 58 patients (44 with Ph-positive ALL, 4 with Burkitt leukemia, 1 with T-ALL, 5 due to exclusion criteria, 1 withdrawal, 1 duplication, and 2 for unknown reasons), 170 patients (83 males and 87 females) remained eligible. The median age was 35 years (range 15-64), and the median white blood cell count was 9.09 x 109/L (range 0.7-547.4). A complete remission (CR) was achieved in 152 (89.4 %) patients. Allogeneic hematopoietic cell transplantation (alloHCT) in CR1 was performed for 50 patients. An additional 29 patients underwent alloHCT not in CR1. With a median follow-up of 5.4 years, the 3-year event-free survival (EFS) and overall survival (OS) rates for eligible patients were 55.1% and 69.1%, respectively. By age group, the 3-year EFS rates for 15-24 years, 25-34 years, 35-44 years, 45-54 years, and 55-64 years were 66.4%, 56.1%, 46.5%, 57.7%, and 40.1%, respectively, showing significant differences. However, the 3-year cumulative incidence of relapse rates did not differ significantly between age groups: 32.8% for 15-24 years, 29.8% for 25-34 years, 32.4% for 35-44 years, 19.6% for 45-54 years, and 44.4% for 55-64 years. Among the 21 CR patients aged 55-64 years, one patient died in CR1, and three patients discontinued the protocol therapy (one at the physician's discretion and two due to adverse events). Regarding prednisolone response, the 3-year EFS of the PGR group was significantly better than that of the PPR group (74.5% vs. 31.2%) in patients aged < 25 years. However, for patients aged ≥ 25 years, the 3-year EFS of PGR and PPR patients did not differ (52.4% vs. 56.6%). According to the modified MRC UKALLXII/ECOG cytogenetic subgroups, the 3-year EFS rates in the standard-, intermediate-, high-, and very high-risk groups were 100%, 56.7%, 83.3%, and 34.3%, respectively. These differences were considered statistically significant. Conclusions Ph (-) B-ALL213, incorporating the PSL prephase and intensified L-ASP regimen, showed better EFS for adult ALL patients including older patients than that in previous reports, although relapse remains a major concern. Our regimen was acceptable for older patients because it reduced the L-ASP dose. The Ph (-) B-ALL213 study suggested that PSL response was not associated with prognosis in adult ALL patients treated with a pediatric-type regimen.