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2813 Utility of a Second Interim Maintenance Phase to Improve Outcomes for Pediatric Acute Lymphoblastic Leukemia: A Report from the Children’s Oncology Group

Program: Oral and Poster Abstracts
Session: 613. Acute Lymphoblastic Leukemias: Therapies Excluding Allogeneic Transplantation: Poster II
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, ALL, Pediatric, Diseases, Therapy sequence, Treatment Considerations, Young adult , Lymphoid Malignancies, Human, Study Population
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Etan Orgel, MD, MS1, Michael J. Burke, MD2*, John A. Kairalla, PhD3, Emily Hibbitts, PhD3*, Meenakshi Devidas, PhD, MBA4, Michael J. Borowitz, MD, PhD5, Brent L. Wood, MD, PhD6,7, Nyla A. Heerema, PhD8*, Andrew J. Carroll, PhD9, Kelly Maloney, MD10*, Leonard A. Mattano, MD11, Anne Angiolillo, MD12*, Eric C. Larsen, MD13*, Wanda L. Salzer, MD14, David T. Teachey, MD15, Naomi J. Winick, MD16, William L. Carroll, MD17, Stephen P. Hunger, MD18, Elizabeth A. Raetz, MD19 and Mignon L. Loh, MD, PhD20

1Cancer and Blood Disease Institute, Children's Hospital of Los Angeles, Los Angeles, CA
2Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI
3University of Florida - Children's Oncology Group, Gainesville, FL
4St Jude Children's Research Hospital, Memphis, TN
5Johns Hopkins University School of Medicine, Baltimore, MD
6Keck School of Medicine of University of Southern California, Los Angeles, CA
7Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA
8Ohio State University, Columbus, OH
9Department of Genetics, University of Alabama at Birmingham, Birmingham, AL
10Children's Hospital Colorado, Aurora, CO
11HARP Pharma Consulting, LLC, Mystic, CT
12Servier Pharmaceuticals, Boston, MA
13Maine Children's Cancer Program, Scarborough, ME
14U.S. Army Medical Research and Materiel Command, Olney, MD
15Division of Oncology, Children's Hospital of Philadelphia, Rutledge, PA
16Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
17Perlmutter Cancer Center, Department of Pediatrics and Pathology, NYU Grossman School of Medicine, New York, NY
18Division of Oncology, Childrens Hospital of Philadelphia, Philadelphia
19Department of Pediatrics, NYU Langone Health, New York, NY
20Ben Towne Center for Childhood Cancer Research, Seattle Children’s Hospital, Fred Hutch Cancer Center, University of Washington, Seattle, WA

Intensification of chemotherapy for pediatric B-cell acute lymphoblastic leukemia (B-ALL) has improved survival. In recently completed Children’s Oncology Group (COG) frontline trials for B-ALL, a second interim maintenance (IM2) phase including escalating dose methotrexate, vincristine, ±pegaspargase was utilized to intensify therapy. On AALL1131 for high risk B-ALL (HR-ALL), very high risk (VHR) patients received IM2. On AALL0932 for standard risk B-ALL (SR-ALL), patients were randomized to steroid/vincristine pulses every 4 (q4weeks) or 12 weeks (q12weeks); all patients received IM2 to maintain treatment intensity in the context of dose-reduced Maintenance therapy. However, the efficacy of IM2 has never been established in either HR-ALL or SR-ALL. Thus, we performed secondary analyses comparing outcomes for matched cohorts treated ±IM2 in sequential COG trials in HR-ALL treated on AALL0232 (no IM2) and AALL1131 (+IM2) and in SR-ALL treated on AALL0331 (no IM2) and AALL0932 (+IM2).

The primary objective was to compare disease-free (DFS) and overall survival (OS) in patients receiving identical systemic COG ALL therapy ±IM2. Secondary objectives were to examine the efficacy of IM2 in SR-ALL with the current standard q12week steroid/vincristine pulses and within cytogenetic subsets. Eligibility criteria for these analyses were designed to match treatment arms between trials. For HR-ALL, inclusion criteria were age ≥13 years old and end of induction (EOI) minimal residual disease (MRD) <0.01%, based on eligibility for the AALL1131 VHR arm. For SR-ALL, patients with neutral or favorable cytogenetics (ETV6::RUNX1 or double trisomies 4 and 10) and EOI MRD <0.01% were included. Patients with BCR::ABL1, KMT2A rearrangement, hypodiploidy, or EOI MRD ≥0.01% were excluded due to treatment variation among trials. Statistical analyses compared DFS and OS via log-rank test and were reported at five years with standard errors. Cox multivariable models analyzed hazard ratios (HR) adjusted for presenting features (demographics, white blood cell count, cytogenetics, central nervous system status).

In HR-ALL, 249 patients from AALL0232 and 65 patients from AALL1131 VHR were eligible. For AALL1131 VHR versus AALL0232, the addition of IM2 was not associated with a difference in DFS (85%±4.7 vs 85%±2.5, p=0.91) or OS (90%±4.0 vs 90%±2.1, p=0.63). In SR-ALL patients receiving q4week pulses in Maintenance, 1,317 patients were eligible from AALL0331 and 1,186 patients from AALL0932. As compared to AALL0331, addition of IM2 in AALL0932 was associated with significantly higher DFS (94%±0.7 vs 91%±0.8, p= 0.0024) and OS (99%±0.4 vs 97%±0.5, p<0.0001). In the Cox multivariable model comparing SR-ALL patients receiving q4week pulses, IM2 significantly decreased risk for an event (HR 0.67, p=0.0048). In SR-ALL patients enrolled in AALL0932 who were randomized to receive q12week pulses (n=1,178), addition of IM2 was associated with higher DFS and OS versus AALL0331 (95%±0.7 vs 91%±0.8, p<0.0001 and 99%±0.3 vs 97%±0.5, p<0.0001, respectively). However, adjusted Cox models demonstrated the decreased event risk was largely in those with neutral cytogenetics (HR=0.62, p=0.0179), with OS (HR=0.58, p=0.0783). No difference in DFS/OS was noted in SR-ALL with favorable cytogenetics.

Within the limitations of unplanned subset analyses, we determined that IM2 may be able to be safely omitted in MRD-negative patients with HR-ALL or with SR-ALL with favorable cytogenetics and that IM2 may provide a survival advantage for patients with SR-ALL, neutral cytogenetics, and MRD <0.01%. Whether IM2 is necessary in patients with higher risk B-ALL due to adverse cytogenetics or persistent MRD was not addressed in these analyses.

Disclosures: Orgel: Jazz Pharma: Consultancy. Wood: Cellnomics LLC: Current equity holder in private company; Amgen: Consultancy. Angiolillo: Servier Pharmaceuticals: Current Employment. Teachey: Jazz: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; BEAM Therapeutics: Research Funding. Carroll: Merck: Consultancy. Hunger: Amgen: Current equity holder in publicly-traded company, Honoraria; Jazz Pharmaceuticals: Honoraria; Servier US: Honoraria; Novartis: Consultancy.

*signifies non-member of ASH