Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: a report from the Children's Oncology Group phase III study AALL0433

Abstract

Outcomes after relapse of childhood B-acute lymphoblastic leukemia (B-ALL) are poor, and optimal therapy is unclear. Children's Oncology Group study AALL0433 evaluated a new platform for relapsed ALL. Between March 2007 and October 2013 AALL0433 enrolled 275 participants with late bone marrow or very early isolated central nervous system (iCNS) relapse of childhood B-ALL. Patients were randomized to receive standard versus intensive vincristine dosing; this randomization closed due to excess peripheral neuropathy in 2010. Patients with matched sibling donors received allogeneic hematopoietic cell transplantation (HCT) after the first three blocks of therapy. The prognostic value of minimal residual disease (MRD) was also evaluated in this study. The 3-year event free and overall survival (EFS/OS) for the 271 eligible patients were 63.6% +/- 3.0% and 72.3% +/- 2.8% respectively. MRD at the end of Induction-1 was highly predictive of outcome, with 3-year EFS/OS of 84.9 +/- 4.0% and 93.8 +/- 2.7% for patients with MRD <0.1%, vs. 53.7 +/- 7.8% and 60.6 +/- 7.8% for patients with MRD ≥0.1% (p<0.0001). Patients who received HCT vs. chemotherapy alone had an improved 3-year disease-free survival (77.5 +/- 6.2% vs. 66.9 +/- 4.5%, p=0.03) but not OS (81.5 +/- 5.8% for HCT vs. 85.8 +/- 3.4% for chemotherapy, p=0.46). Patients with early iCNS relapse fared poorly, with a 3-year EFS/OS of 41.4% +/- 9.2% and 51.7% +/- 9.3%, respectively. Infectious toxicities of the chemotherapy platform were significant. The AALL0433 chemotherapy platform is efficacious for late bone marrow relapse of B-ALL, but with significant toxicities. The MRD threshold of 0.1% at the end of Induction-1 was highly predictive of outcome. The optimal role for HCT for this patient population remains uncertain. This trial is registered at clinicaltrials.gov (NCT# 00381680).

Trial registration: ClinicalTrials.gov NCT00381680.

Figure 1.

Schema. CNS: central nervous system; VCR: Vincristine; CSF: cerebrospinal fluid; ITT: intention-to-treat ; HLA: human leukocyte antigen; SCT: stem cell transplant.

Figure 2.

CONSORT Diagram. BM: bone marrow; HCT: hematopoietic cell transplantation; CR2: second complete remission; CNS: central nervous system; Ph-ALL: Philadelphia chromosome–like acute lymphoblastic leukemia; MPAL: mixed phenotype acute leukemia.

Figure 3.

Overall outcomes for all eligible patients. (A) Event-free survival (EFS) curves, 3-year and 5-year EFS: 63.6±3.0%, and EFS 51.0%±3.5%, respectively. (B) Overall survival (OS), 3-year and 5-year OS 72.3±2.8%, and OS 62.9±3.3%, respectively.

Figure 4.

Survival curves by 0.1% minimal residual disease (MRD) threshold after induction-1 for late bone marrow relapse patients on standard arm (Arm A), with available MRD data. (A) Event-free survival (EFS) curves by 0.1% MRD threshold, 3-year EFS: 84.9±4.0% for patients with MRD <0.1% versus 53.7±7.8% for patients with MRD ≥0.1% (P<0.0001). (B) Overall survival (OS) curves by 0.1% MRD threshold, 3-year OS: 93.8±2.7% for patients with MRD <0.1% and 60.6±7.8% for patients with MRD ≥0.1% (P<0.0001).

Figure 5.

Survival curves by hematopoietic cell transplantation versus chemotherapy alone, for late bone marrow relapse patients on Arm A. (A) Adjusted disease-free survival (DFS) curves by hematopoietic cell transplantation (HCT) versus chemotherapy alone, 3-year DFS: 77.5±6.2% for HCT and 66.9±4.5% for chemotherapy alone (P=0.03). One relapse occurred after 6 years, where only two patients had more than 6 years of follow-up, which resulted in DFS for HCT dropping from 77.5% to 38.8%. (B) Adjusted overall survival (OS) curves by HCT versus chemotherapy alone, 3-year OS: 81.5±5.8% for HCT and 85.8±3.4% for chemotherapy alone (P=0.46).

Figure 6.

Survival curves by hematopoietic cell transplantation versus chemotherapy alone, for late bone marrow relapse patients on Arm A, using a 0.1% minimal residual disease threshold. (A) Adjusted disease-free survival (DFS) curves for minimal residual disease (MRD) <0.1%, by hematopoietic cell transplantation (HCT) versus chemotherapy alone, 3-year DFS: 90.7±6.5% for HCT and 74.1±5.8% for chemotherapy alone (P=0.07). (B) Adjusted overall survival (OS) curves for MRD <0.1%, by HCT versus chemotherapy alone, 3-year OS: 95.5±4.7% for HCT and 93.1±3.4% for chemotherapy alone (P=0.16). (C) Adjusted disease-free survival (DFS) curves for MRD ≥0.1%, by HCT versus chemotherapy alone, 3-year DFS: 56.3±13.2% for HCT and 55.0± 11.1% for chemotherapy alone (P=0.23). (D) Adjusted OS curves for MRD ≥0.1%, by HCT versus chemotherapy alone, 3-year OS: 62.5±12.8% for HCT and 70.0±10.3% for chemotherapy alone (P=1.00).