Reinduction platform for children with first marrow relapse of acute lymphoblastic Leukemia: A Children's Oncology Group Study[corrected]

Abstract

Purpose: Treatment of childhood relapsed acute lymphoblastic leukemia (ALL) remains a significant challenge. The goal of the Children's Oncology Group (COG) AALL01P2 study was to develop a safe and active chemotherapy reinduction platform, which could be used to evaluate novel agents in future trials.

Patients and methods: One hundred twenty-four patients with ALL and first marrow relapse received three, 35-day blocks of reinduction chemotherapy: 69 with early relapse (ER; < 36 months from initial diagnosis) and 55 with late relapse (LR). Minimal residual disease (MRD) was measured by flow cytometry after each treatment block.

Results: Second complete remission (CR2) rates at the end of block 1 in 117 assessable patients were 68% +/- 6% for ER (n = 63) and 96% +/- 3% for LR (n = 54; P < .0001). Five of seven patients with T-cell ALL (T-ALL) failed to achieve CR2. Among patients in CR2, MRD greater than 0.01% was detected at the end of block 1 in 75% +/- 7% of ER (n = 36) versus 51% +/- 8% of LR (n = 43; P = .0375) and 12-month event-free survival was 80% +/- 7% versus 58% +/- 7% in MRD-negative versus positive patients (P < .0005). Blocks 2 and 3 of therapy resulted in reduction of MRD burden in 40 of 56 patients who were MRD positive after block 1. Toxicity was acceptable during all three blocks with five deaths (4%) from infections.

Conclusion: The AALL01P2 regimen is a tolerable and active reinduction platform, suitable for testing in combination with novel agents in B-precursor ALL. Alternative strategies are needed for T-ALL. Serial MRD measurements were feasible and prognostic of outcome.

Fig A1.

Minimal residual disease (MRD) response rates according to timing of relapse (online only). MRD responses after the second and third blocks of therapy are shown in this flow diagram in those patients achieving CR2 at the end of block 1. At the end of three blocks of therapy, 16 (33%) of 49 of patients overall, remained MRD positive. Note that one patient with an M1 marrow at the end of block 1 (day 36) was determined not to be in CR2 due to absence of count recovery on day 36 and an M3 marrow 1 week later, and was excluded from this analysis. Among 18 patients with M2 or M3 marrows at the end of block 1, 13 did not achieve remission despite the administration of the second block of chemotherapy. Five entered remission with ongoing chemotherapy; however, four of these five patients developed disease recurrence within 1 year. NT, not tested.

Fig 1.

Outcomes based on site and timing of recurrence. Outcomes after first isolated or combined marrow relapse. (A) Overall event-free survival (EFS) of all patients enrolled after the study was amended for initial toxicity. (B) EFS according to timing of relapse in all patients. (C) Overall EFS of B-precursor, CNS-negative, Philadelphia chromosome-negative patients. (D) EFS according to timing of relapse in B-precursor, CNS-negative, Philadelphia chromosome-negative patients. (B, D) Solid line = early relapse (< 36 months from initial diagnosis), dashed line = late marrow relapse (≥ 36 months from initial diagnosis).

Fig 2.

Outcomes according to block 1 minimal residual disease (MRD) response. Event-free survival (EFS) probabilities for patients in morphological CR2 who were MRD negative versus positive at the end of block 1. (A) All patients: 12-month EFS 80% ± 7% versus 58% ± 7% in MRD-negative versus MRD-positive patients. (B) Early marrow relapse: 12-month EFS 67% ± 16% versus 42% ± 10% for MRD-negative versus -positive patients. (C) Late marrow relapse: 12-month EFS 86% ± 8% versus 77% ± 9% in MRD-negative versus -positive patients.

Fig 3.

Kinetics of minimal residual disease (MRD). MRD was measured after each block of therapy and four general response patterns were observed among 77 patients with MRD data for multiple time points. R1 patients included those negative at all time points tested; R2 included those who became negative after either block 2 or block 3; R3 included those patients who decreased but still had detectable disease at the end of the final block of therapy; and R4 included patients showed no decline or rising MRD. The 12-month EFS probabilities for the four groups were 86% ± 8%, 73% ± 8%, 70% ± 16%, and 19% ± 10%, respectively.