Outcomes in children with NCI standard-risk b-acute lymphoblastic leukemia treated with intensified post-induction therapy: Results from Children's Oncology Group studies AALL0932 and AALL1131

Abstract

Abstract Introduction End of induction (EOI) positive minimal residual disease (MRD) and unfavorable sentinel genetic lesions predict poor outcomes for patients with B-cell acute lymphoblastic leukemia (B-ALL). We examined outcomes for patients with newly diagnosed NCI standard risk (SR) B-ALL enrolled on AALL0932 who were stratified as high risk (HR) or very high risk (VHR) post-induction based on MRD and/or unfavorable genetic features. Patients and methods Children (n = 9277) with newly diagnosed NCI SR B-ALL (age 1-9.99 years and initial white blood cell count <50,000/microliter) were enrolled on AALL0932 (2010-2018). They received a 3-drug, 4-week induction and were subsequently classified into different risk groups for post-induction therapy. We examined disease-free (DFS) and overall survival (OS) of 2295 HR or VHR patients. HR patients had favorable cytogenetics (ETV6::RUNX1 or double trisomies of chromosomes 4+10) and EOI MRD ≥0.01% or no favorable cytogenetics with day 8 peripheral blood MRD ≥1% and EOI MRD < 0.01%. VHR patients had unfavorable cytogenetics (intrachromosomal amplification of chromosome 21, KMT2A-rearrangement, hypodiploidy), and/or induction failure (M3) and/or no favorable cytogenetics and EOI MRD ≥0.01%. These HR/VHR patients were ineligible to continue AALL0932 therapy but were eligible to enroll on the COG AALL1131 trial (2012- 2019) post-induction. Intensified post-induction AALL1131 therapy utilized an augmented BFM therapy backbone with randomizations testing different intrathecal therapy strategies (HR) and consolidation chemotherapy regimens (VHR). Those not enrolled on AALL1131 were treated off protocol therapy at physician discretion. Patients with Down syndrome or BCR::ABL1 were not eligible for post-induction enrollment on AALL1131. Results At AALL0932 EOI, 1262 (13.7%) patients were classified as HR and 1033 (11.2%) patients as VHR. Most patients had CNS1 status at diagnosis (HR patients 1153, 91.4%; and VHR patients 908, 87.9%) and the remainder were CNS2 (CNS3 patients were ineligible for AALL0932). 708 HR patients (56.1%) had favorable cytogenetics, 311 VHR patients (30.1%) had unfavorable cytogenetics, and the remainder in both groups had neutral cytogenetics. EOI MRD ≥ 0.01% was detected in 705 (55.9%) HR and 820 (79.4%) VHR patients. Overall, these HR and VHR NCI SR B-ALL patients had 7-year post-induction DFS and OS rates (±SE) of 85.3 ± 1.0% and 94.1 ± 0.6%. In outcome analyses stratified by risk group, no differences in outcomes were seen for the HR or VHR patients enrolled or not on AALL1131. For HR patients treated on (693, 54.9%) vs not on AALL1131: 7-year DFS 92.1 ± 1.3% vs. 91.2 ± 1.5% (P = 0.70) and 7-year OS 97.8 ± 0.7% vs. 97.1 ± 0.9% (P = 0.58). For VHR patients enrolled on (217, 21.0%) vs not on AALL1131: 7-year DFS 76.1 ± 3.9% vs. 77.4 ± 1.9% (P = 0.95) and 7-year OS 91.9 ± 2.5% vs. 89.3 ± 1.4% (P = 0.32). Temporary suspensions of AALL1131, in part due to unexpected toxicities on the VHR arm, contributed to non-enrollment of AALL0932 HR/VHR patients for AALL1131 post-induction therapy. Conclusion Following treatment with a 3-drug induction, clinical outcomes for children with NCI SR B-ALL that were EOI MRD-positive or had unfavorable genetics, are excellent with intensified, high risk augmented BFM post-induction therapy. We anticipate that outcomes for these patients will improve further with addition of blinatumomab in ongoing and future clinical trials.