Augmented therapy improves outcome for pediatric high risk acute lymphocytic leukemia: results of Children's Oncology Group trial P9906

Abstract

Background: The augmented BFM regimen improves outcome for children with NCI high acute lymphoblastic leukemia (ALL). Patient age, sex, and presenting white blood cell count (WBC) can be used to identify a subset of approximately 12% of children with B-precursor ALL that had a 5-year continuous complete remission (CCR) rate of only about 50% on earlier Pediatric Oncology Group (POG) trials.

Procedures: Children's Oncology Group trial P9906 evaluated a modified augmented BFM regimen in 267 patients with particularly high risk B-precursor ALL. Minimal residual disease (MRD) was assessed in blood at day 8 and in marrow at day 29 of induction and correlated with outcome.

Results: The 5-year CCR probability for patients in P9906 was significantly better than that observed for similar patients on POG trials 8602/9006 (62.2 ± 3.7% vs. 50.6 ± 2.4%; P = 0.0007) but similar to POG 9406 (63.5 ± 2.4%; P = 0.81). Interim analysis showed poor central nervous system (CNS) control, especially in patients with initial WBC ≥ 100,000/microliter. Day 29 marrow MRD positive (≥ 0.01%) vs. negative patients had 5 year CCR rates of 37.1 ± 7.4% vs. 72.6 ± 4.3%; day 8 blood MRD positive vs. negative patients had 5 year CCR rates of 57.1 ± 4.6% vs.83.6 ± 6.3%. End induction marrow MRD predicted marrow but not CNS relapse. In multivariate analysis, day 29 MRD > 0.01%, initial WBC ≥ 100,000/µl, male gender, and day 8 blood MRD > 0.01% were significant prognostic factors.

Conclusions: Augmented BFM therapy improved outcome for children with higher risk ALL. Day 8 blood and day 29 marrow MRD were strong prognostic factors in these patients.

Figure 1

Kaplan-Meyer curves comparing the continuous complete remission rates of patients treated on COG P9906 with that of historical controls (similarly-defined subset of high risk patients treated on prior POG protocols 8602, 9006, and 9406). Study 8602 enrolled 1933 patients with ALL, 251 of which had the comparable high risk characteristics of patients in 9906; study 9006 enrolled 614 patients with high risk ALL, with 235 having matching characteristics; and study 9406 enrolled 786 high risk patients with 437 with comparable characteristics. The 5 y CCR rate on 9906 was 62.2±3.7% compared to 50.6±2.4% for the relevant comparison group on 8602/9006 and 63.5±2.4% on 9406.

Figure 2

Kaplan-Meyer curves displaying the outcome of patients based on the level of bone marrow MRD at day 29 of induction therapy (A) and on the level of blood MRD at day 8 of induction therapy. (B) A. Patients with <0.01% marrow MRD had a 72.6±4.3% 5 year CCR rate while those with increasing levels of MRD generally showed an increasingly bad outcome. The 5 year CCR of all patients positive at 0.01% or greater at day 29 was 37.1±7.4%. B. Patients with <0.01% day 8 blood MRD had a 83.6±6.3% 5 year CCR rate while those with increasing levels of MRD showed an increasingly bad outcome, with those patients with 1% < MRD ≤ 10% in the blood at day 8 having a 55.6±10.0% 5 year CCR rate and those with >10% having a 5 y CCR rate of 25.1±12.5%. Overall, 80% of patients had blood MRD positive at 1% or greater at day 8, and 5 year CCR rate was 57.1±4.6% for these patients.

Figure 3

Independent effect of day 29 MRD and that of initial white blood cell count on the outcome of patients. The 5 y CCR rate for MRD negative patients with WBC<100,000/µl was 79.7±4.8%, while those who were MRD positive with a WBC≥100,000/µl was 27.7±11.8%. Patients with <100,000 WBC/µl who were MRD positive, or those with WBC≥100,000/ul and MRD negative had intermediate outcomes with 42.7±9.3% and 58.4±8.2% 5 y CCR respectively (p<0.0001). In subset analyses, elevated WBC was associated with significantly worse outcome in both the MRD negative (p=0.0049) and MRD positive patients (p=0.0063). Similarly, MRD positivity was associated with significantly worse outcome in both the lower (p<0.0001) and higher (p=0.027) WBC patients.

Figure 4

Cumulative incidence of marrow (A) and non-marrow (B) relapse of patients based on end of induction MRD status. Patients with at least .01% marrow MRD had a nearly 4 fold increased risk of marrow relapse at 5 years, at 48.8±5.8% compared to 13.0±2.8% for those who were MRD negative. The 5 year cumulative incidence of non marrow relapse was 12% in both the MRD positive and negative groups.