Dexamethasone exposure and asparaginase antibodies affect relapse risk in acute lymphoblastic leukemia

Abstract

We have previously hypothesized that higher systemic exposure to asparaginase may cause increased exposure to dexamethasone, both critical chemotherapeutic agents for acute lymphoblastic leukemia. Whether interpatient pharmaco-kinetic differences in dexamethasone contribute to relapse risk has never been studied. The impact of plasma clearance of dexamethasone and anti-asparaginase antibody levels on risk of relapse was assessed in 410 children who were treated on a front-line clinical trial for acute lymphoblastic leukemia and were evaluable for all pharmacologic measures, using multivariate analyses, adjusting for standard clinical and biologic prognostic factors. Dexamethasone clearance (mean ± SD) was higher (P = 3 × 10(-8)) in patients whose sera was positive (17.7 ± 18.6 L/h per m(2)) versus nega-tive (10.6 ± 5.99 L/h per m(2)) for anti-asparaginase antibodies. In multivariate analyses, higher dexamethasone clearance was associated with a higher risk of any relapse (P = .01) and of central nervous system relapse (P = .014). Central nervous system relapse was also more common in patients with anti-asparaginase antibodies (P = .019). In conclusion, systemic clearance of dexamethasone is higher in patients with anti-asparaginase antibodies. Lower exposure to both drugs was associated with an increased risk of relapse.

Figure 1

Consort diagram. A total of 498 children were enrolled on frontline protocol Total XV. Of these, 410 patients (pts) had evaluable anti–asparaginase antibody (Ab), and 339 patients had evaluable dexamethasone apparent oral clearance data, measured at week 8 of continuation phase of therapy. Dexamethasone pharmacokinetics were previously reported for a subset of 214 patients.

Figure 2

Overview of asparaginase and glucocorticoid dosing, and sample collection for dexamethasone pharmacokinetics and anti–asparaginase antibody measurement. Patients received prednisone (PRED) at 40 mg/m² per day during remission induction. Dexamethasone (DEX) was administered at 12 mg/m² per day (SR/HR arm) and 8 mg/m² per day (LR arm) in 5-day blocks during continuation weeks 1, 4, and 14; and at 8 mg/m² on days 1 to 8 and 15 to 21 during reinduction I (weeks 7-9 of continuation) and reinduction II (weeks 17-19 of continuation) for both risk groups. Asparaginase (L-ASP) at 10 000 U/m² per dose was administered to all patients during remission induction at days 6, 8, 10, 12, 14, and 16 (and at days 19, 21, and 23 for those with ≥ 1% residual leukemia cells in bone marrow on day 19). During the continuation phase, those in SR/HR arms received 25 000 U/m² once per week from weeks 1 to 19; those in the LR arm received 10 000 U/m² thrice weekly at weeks 7 to 9 and 17 to 19. Anti–asparaginase antibodies (ANTI–ASP) were determined on days 5, 19, and 34 of remission induction and day 1 of weeks 7 and 19 of continuation therapy, and dexamethasone pharmacokinetics (PK) were determined on day 1 of week 8 of continuation therapy.

Figure 3

Dexamethasone clearance was affected by age and treatment risk group. Association of dexamethasone apparent oral clearance with age (A), treatment arm (B), sex (C), and race (D).

Figure 4

Patients with anti–asparaginase antibodies had higher dexamethasone clearance. Patients who tested positive for anti–asparaginase antibodies had (A) higher dexamethasone clearance and (B) lower dexamethasone exposure (AUC). The level of anti–asparaginase antibodies over time (AUC) was correlated directly with dexamethasone clearance (C) and inversely with dexamethasone plasma exposure (D).

Figure 5

Cumulative incidence of relapse based on dexamethasone clearance and anti–asparaginase antibody status. Cumulative incidence of CNS relapse (A) and any (hematologic, CNS, combined, and other) relapse (B) in patients who became positive (N = 207) versus those who remained negative (N = 132) for anti–asparaginase (ASP) antibodies with P values based on multivariate analysis (Table 1). Cumulative incidence of CNS relapse (C) and any relapse (D) in patients with dexamethasone (Dex) clearance (CL) greater than (N = 12) versus lower (N = 327) than 37.5 L/h per m² with P values based on log-rank test.