Augmented use of L-asparaginase markedly improves AYA ALL outcomes: FBMTG prospective MRD2014 study

Abstract

The enhanced utilization of native L-asparaginase (L-Asp) aims to improve treatment outcomes for adult patients with non-Philadelphia chromosome (Ph) acute lymphoblastic leukemia (ALL). In this measurable residual disease 2014 (MRD2014) study, we modified our protocol to include an augmented dose of native L-Asp. Compared with former MRD2008, the total dose of L-Asp was raised from 36 000 U/m² to 232 000 U/m² in patients aged 16 to 35 and from 36 000 U/m² to 132 000 U/m² in patients aged 36 to 65 years. Adult patients with ALL were enrolled between January 2014 and December 2019 based on the following eligibility criteria: non-L3 ALL, age 16 to 65 years, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate liver and kidney functions (serum bilirubin ≤ 2.0 mg/dL; serum creatinine ≤ 2.0 mg/dL). The median follow-up time was 1128 days (range, 35-2400). A total of 81 patients with non-Ph ALL (40 males and 41 females; median age, 39 years [range, 16-64]) in whom MRD status was assessed were included. Complete remission was achieved in 72 patients (89%). The probability of 3-year event-free survival (EFS) and overall survival (OS) in these patients were 55% and 72%, respectively. The outcomes for patients aged 16 to 35 years demonstrated remarkable improvement. The 3-year EFS of MRD2008 at 45% significantly increased to 71% for MRD2014. Our study unequivocally demonstrated the beneficial effects of augmented use of L-Asp in this adolescent and young adult population. This trial was registered at UMIN Clinical Trials Registry as #UMIN000012382.

Graphical abstract

Figure 1.

Flow description of the results of the treatment program (ALL MRD2014 study). A total of 164 adult patients with ALL were enrolled in this study between January 2014 and December 2019. Of the 164 patients enrolled, 61 were excluded from the study because of Ph positivity and 5 due to misdiagnosis. The remaining 98 patients were Ph^–; among them, MRD could be evaluated in 81 patients. We used a modified CALGB 19802 treatment protocol that comprised 6 courses of chemotherapy administered in the order of A-B-C-A-B-C regimens, followed by a maintenance phase. MRD status was assessed in our study at 2 critical points: first, after the induction therapy (first course A1), denoted as the EOI; and second, after the second consolidation therapy (first course C), referred to as the EOC. EOC MRD-positive patients were considered to be indicated for allogeneic hematopoietic stem cell transplantation (HSCT) as soon as possible. BM, bone marrow; CNS, central nervous system; EM, extramedullary.

Figure 2.

EFS and OS by patient age group. Analyzing the survival rates by patient age groups (16-35, 36-55, and 56-65 years), the probability of 3-year EFS and OS were as follows: for EFS, 71% (95% CI, 52-83) vs 50% (95% CI, 32-66) vs 23% (95% CI, 6-48; P = .001); and for OS, 85% (95% CI, 68-94) vs 69% (95% CI, 50-82) vs 46% (95% CI, 20-70; P < .001), respectively.

Figure 3.

Impact of EOI MRD status on EFS and OS. In terms of CR1 status, 3-year EFS was 68% (95% CI, 50-80) in EOI MRD-negative patients and 36% (95% CI, 19-53) in EOI MRD-positive patients (P = .012). Three-year OS was 84% (95% CI, 68-92) in EOI MRD-negative patients (n = 38) and 54% (95% CI, 30-67) in EOI MRD-positive patients (n = 29; P = .020).

Figure 4.

EFS by patient age group, comparing MRD2008 and MRD2014. The treatment outcomes of patients aged 16 to 35 years were remarkably improved. Compared with the 3-year EFS of MRD2008 (n = 30) of 45% (95% CI, 27-62), the 3-year EFS of MRD2014 (n = 34) of 71% (95% CI, 52-83) was significantly improved (P = .038). In contrast, there were no significant difference in 3-year EFS in patients aged 36 to 55 years, 69% (95% CI, 37-87) vs 50% (95% CI, 32-66; P = .508); and with patient aged 56 to 65 years, 37% (95% CI, 9-67) vs 23% (95% CI, 6-48; P = .226), respectively.