Pegaspargase-modified risk-oriented program for adult acute lymphoblastic leukemia: results of the GIMEMA LAL1913 trial.

Pediatric-inspired chemotherapy is the standard of care for younger adults with Philadelphia-negative acute lymphoblastic leukemia/lymphoma (Ph- ALL/LL). The GIMEMA LAL1913 trial tested a modified regimen adding pegaspargase 2000 IU/m2 to courses 1, 2, 5 and 6 of an eight-block protocol for patients 18-65 years, with dose reductions in patients >55 years. Responders were risk-stratified to allogeneic hematopoietic stem cell transplantation (HCT) or maintenance according to clinical characteristics and minimal residual disease (MRD). Out of 203 study patients (median age 39.8 years, 68.5% B-lineage), 185 (91%) achieved a complete remission (CR). The 3-year overall survival (OS), event-free (EFS) and disease-free (DFS) survival rates were 66.7% (95% confidence intervals, 64.4-60.1%), 57.7% (51.0-65.3%) and 63.3% (56.3-71.1%), respectively, fulfilling the primary study endpoint of a 2-year DFS >55%. While by intention-to-treat DFS was 74% and 50% in the chemotherapy (n=94) and HCT (n=91) assigment cohorts, a time-dependent analysis proved the value of HCT in eligible patients (DFS HCT 70% vs. no HCT 26%, P<0.0001). In multivariate analysis, age and MRD (n=151) were independent prognostic factors associated with DFS rates of 86% (age less/equal to 40/MRD-negative, n=66), 65% (age >40/MRD-negative, n=48), 64% (age less/equal to 40/MRD-positive, n=17) and 25% (age >40/MRD-positive, n=20) (P<0.0001). Grade 2/greater pegaspargase toxicity was mainly observed at course 1 (41 episodes in 32 patients), contributing to induction death in 2 patients, but was rare and milder thereafter. This pegarspargase-containing risk-oriented program was feasible and improved outcome of Ph- ALL/LL patients up to 65 years in a multicenter national setting. ClinicalTrials.gov #NCT02067143.