Eflornithine as Postimmunotherapy Maintenance in High-Risk Neuroblastoma: Externally Controlled, Propensity Score-Matched Survival Outcome Comparisons

Abstract

Purpose: Long-term survival in high-risk neuroblastoma (HRNB) is approximately 50%, with mortality primarily driven by relapse. Eflornithine (DFMO) to reduce risk of relapse after completion of immunotherapy was investigated previously in a single-arm, phase II study (NMTRC003B; ClinicalTrials.gov identifier: NCT02395666) that suggested improved event-free survival (EFS) and overall survival (OS) compared with historical rates in a phase III trial (Children Oncology Group ANBL0032; ClinicalTrials.gov identifier: NCT00026312). Using patient-level data from ANBL0032 as an external control, we present new analyses to further evaluate DFMO as HRNB postimmunotherapy maintenance.

Patients and methods: NMTRC003B (2012-2016) enrolled patients with HRNB (N = 141) after standard up-front or refractory/relapse treatment who received up to 2 years of continuous treatment with oral DFMO (750 ± 250 mg/m² twice a day). ANBL0032 (2001-2015) enrolled patients with HRNB postconsolidation, 1,328 of whom were assigned to dinutuximab (ch.14.18) treatment. Selection rules identified 92 NMTRC003B patients who participated in (n = 87) or received up-front treatment consistent with (n = 5) ANBL0032 (the DFMO/treated group) and 852 patients from ANBL0032 who could have been eligible for NMTRC003B after immunotherapy, but did not enroll (the NO-DFMO/control group). The median follow-up time for DFMO/treated patients was 6.1 years (IQR, 5.2-7.2) versus 5.0 years (IQR, 3.5-7.0) for NO-DFMO/control patients. Kaplan-Meier and Cox regression compared EFS and OS for overall groups, 3:1 (NO-DFMO:DFMO) propensity score-matched cohorts balanced on 11 baseline demographic and disease characteristics with exact matching on MYCN, and additional sensitivity analyses.

Results: DFMO after completion of immunotherapy was associated with improved EFS (hazard ratio [HR], 0.50 [95% CI, 0.29 to 0.84]; P = .008) and OS (HR, 0.38 [95% CI, 0.19 to 0.76]; P = .007). The results were confirmed with propensity score-matched cohorts and sensitivity analyses.

Conclusion: The externally controlled analyses presented show a relapse risk reduction in patients with HRNB treated with postimmunotherapy DFMO.

FIG 1.

Study flow for the two individual clinical trials, NMTRC003B and ANBL0032. NMTRC003B is a phase II, open-label, single-dose level evaluation of 2-year maintenance treatment with DFMO in patients with HRNB in remission at the end of immunotherapy (stratum 1). Data from the independent ANBL0032 study were used as an external control for NMTRC003B to evaluate survival differences in a comparable group of eligible patients: those in remission at the end of dinutuximab immunotherapy treated with DFMO in NMTRC003B versus those who did not receive DFMO and continued follow-up without further pharmacotherapy as per current SoC in ANBL0032. Patients in ANBL0032 completed high-risk induction chemotherapy and surgery (as indicated), consolidation comprised at least one ASCT (within 12 months of high-risk induction start) and radiation (as indicated), and received dinutuximab immunotherapy on study (within 200 days from ASCT). Patients in NMTRC003B completed high-risk induction chemotherapy and surgery (as indicated), consolidation therapy (ASCT and radiation therapy, as indicated), and immunotherapy with anti-GD2 antibody (eg, dinutuximab), and achieved end of immunotherapy response of at least PR with no evidence of disease in the bone marrow on the basis of institutional assessment (Data Supplement, Table S1). Both studies followed patients for EFS and OS as end points. Protocol-required imaging was similar during follow-up/surveillance for both studies. ASCT, autologous stem-cell transplant; DFMO, eflornithine; EFS, event-free survival; HRNB, high-risk neuroblastoma; OS, overall survival; PR, partial response; SoC, standard of care.

FIG 2.

Selection rules specific and applied to each study group (A) and rationale for the selection criteria (B). NMTRC003B comprised N = 141 patients in remission at the end of standard up-front, refractory, or relapse therapy and receiving DFMO treatment (up to 2 years) in NMTRC003B or its identically designed predecessor trial. Eligibility criteria were intentionally aligned with patients who completed treatment in ANBL0032 (Data Supplement, Table S1; patients were enrolled during 2012-2016 and long-term follow-up is ongoing with data cutoff for analyses: June 30, 2021). The ANBL0032 database comprised 1,328 dinutuximab-treated patients (excluding those initially randomly assigned to RA alone) obtained via a data transfer agreement with COG (patients were enrolled during 2001-2015, and long-term follow-up is ongoing with data cutoff for analyses: June 30, 2019). The final DFMO/test population (n = 92) only comprised patients who had enrolled in or received treatment consistent with ANBL0032 before DFMO treatment. The NO-DFMO/control population (n = 852) comprised patients eligible to enroll in NMTRC003B (stratum 1) after dinutuximab immunotherapy completion, including patients consistent with the NMTRC003B operational definition of remission (ie, overall end of immunotherapy response ≥PR and negative for bone marrow disease 30 days after immunotherapy), and excluded patients at end-of-immunotherapy PR without a bone marrow evaluation (not performed/missing in the database). ^aOne compassionate use patient was excluded from the efficacy analysis at the time of enrollment (per protocol). ^bPatient data for the predecessor trial are reported via the chart review study BCC001, which was combined with the NMTRC003B study database for analysis. ^cResponse criteria 2 and 3 for ANBL0032 and NMTRC003B, respectively, followed modified INRC 1993 international guidelines. ASCT, autologous stem-cell transplant; COG, Children Oncology Group; DFMO, eflornithine; dinutuximab, anti-GD2 antibody therapy; EFS, event-free survival; HRNB, high-risk neuroblastoma; NED, no evidence of disease; NO-DFMO, no eflornithine (control); PR, partial response; RA, 13-cis-retinoic acid.

FIG 3.

CONSORT diagram. Comparative cohort selection from NMTRC003B and the independent study ANBL0032. Matching ratio defined as 3 NO-DFMO/control : 1 DFMO/test. ASCT, autologous stem-cell transplant; BM, bone marrow; DFMO, eflornithine; dinutuximab, anti-GD2 antibody therapy; EFS, event-free survival; HR, hazard ratio; HRNB, high-risk neuroblastoma; NED, no evidence of disease; NO-DFMO, no eflornithine (control); OS, overall survival; PR, partial response; PSM, propensity score matching.

FIG 4.

Survival outcomes in the overall (unmatched) study populations. KM curves with 4-year KM estimates (±SE) in the overall study populations (unmatched) for (A) EFS and (B) OS and corresponding sensitivity analyses to (C and D) limit NO-DFMO patients to those with CR end of immunotherapy response and the (E and F) contemporary treatment era (removing patients receiving immunotherapy before 2011). CR, complete response; DFMO, eflornithine; EFS, event-free survival; HR, hazard ratio; KM, Kaplan-Meier; NO-DFMO, no eflornithine (control); OS, overall survival.

FIG 5.

Survival outcomes in the matched study populations. KM curves with 4-year KM estimates (±SE) in the matched study populations for (A) EFS and (B) OS and corresponding sensitivity analyses to limit NO-DFMO patients to those with end of immunotherapy response (C and D) and the (E and F) contemporary treatment era (removing patients receiving immunotherapy before 2011). The contemporary sensitivity analysis is shown with a 2:1 matching ratio; contemporary patients with complete covariate data for PSM reduced the control population to n = 370. The 3:1 ratio forced selection of 270 patients with resulting covariate imbalances, requiring a reduction in the ratio to achieve proper balance. DFMO, eflornithine; EFS, event-free survival; HR, hazard ratio; KM, Kaplan-Meier; NO-DFMO, no eflornithine (control); OS, overall survival; PR, partial response; PSM, propensity score–matching; VGPR, very good partial response.