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824 Patients with Down Syndrome and High-Risk B-Acute Lymphoblastic Leukemia Demonstrate Improved Outcomes on a Modified Chemotherapy Regimen: A Report from Children’s Oncology Group Study AALL1131

Program: Oral and Poster Abstracts
Type: Oral
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Optimal Frontline Treatment for ALL
Hematology Disease Topics & Pathways:
Research, clinical trials, Lymphoid Leukemias, ALL, Clinical Research, Combination therapy, pediatric, Diseases, Therapies, Lymphoid Malignancies, Adverse Events, young adult , Study Population, Human, Minimal Residual Disease
Monday, December 11, 2023: 3:00 PM

Vilmarie Rodriguez, MD1, Meenakshi Devidas, PhD, MBA2, Zhiguo (Bruce) Chen, MS3*, Andrew J Carroll, PhD4, Nyla A. Heerema, PhD5*, Michael J. Borowitz, MD, PhD6, Brent L. Wood, MD, PhD7, William L. Carroll, MD8, Naomi J Winick, MD9*, Elizabeth A. Raetz10*, Mignon L. Loh, MD11, Michael J. Burke, MD12*, Wanda L. Salzer, MD13, Stephen P. Hunger, MD14 and Karen R. Rabin, MD, PhD15

1Division of Pediatric Hematology/Oncology/Blood and Bone Marrow Transplant, Nationwide Children's Hospital/The Ohio State University, Columbus, OH
2St Jude Children's Research Hospital, Memphis, TN
3Biostatistics, University of Florida, Gainesville, FL
4Department of Genetics, University of Alabama at Birmingham, Birmingham, AL
5Ohio State University, Columbus, OH
6Johns Hopkins University School of Medicine, Baltimore, MD
7Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA
8Perlmutter Cancer Center, Department of Pediatrics and Pathology, NYU Grossman School of Medicine, New York, NY
9Simmons Cancer Center and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
10New York University Langone Medical Center, New York, NY
11Ben Towne Center for Childhood Cancer Research, Seattle Children’s Hospital, Seattle, WA
12The Medical College of Wisconsin Inc, Milwaukee, WI
13U.S. Army Medical Research and Materiel Command, Fort Detrick, MD
14Childrens Hospital of Philadelphia, Philadelphia
15Department of Pediatrics, Baylor College of Medicine, Baylor College of Medicine TX Children's Cancer Center, Houston, TX

Introduction: Children with Down syndrome (DS) have a 20-fold increased risk of developing B-acute lymphoblastic leukemia (B-ALL), and demonstrate an increased risk of both relapse and treatment-related mortality (TRM). The Children’s Oncology Group (COG) High-Risk (HR) B-ALL trial AALL0232 was permanently closed to DS HR patients due to excessive TRM, primarily due to overwhelming sepsis during times of severe neutropenia. On the successor HR B-ALL trial AALL1131, a primary objective for DS patients was therefore to reduce TRM by enhancing supportive care and modifying some elements of therapy.

Methods: DS HR patients were treated on a single non-randomized stratum, with several modifications compared to non-DS HR patients. The majority of DS HR patients received a three-drug Induction, with only slow early responders (M2/M3 marrow at Induction day 15) receiving a single dose of anthracycline (daunorubicin 50 mg/m2). Interim Maintenance 1 (IM-1) consisted of four IV courses of intermediate dose (ID; 2,000 mg/m2) rather than high-dose methotrexate (HD MTX; 5,000 mg/m2), with leucovorin rescue beginning earlier, at hour 30 and advancing if tolerated to hour 36, rather than at hour 42. Maintenance modifications included administration of vincristine/steroid pulses every 12 instead of every 4 weeks, and equal duration of therapy for boys and girls.

Results: Patient characteristics (Table 1) were similar among the 280 DS HR patients and 5,612 non-DS HR patients except for more frequent bone marrow minimal residual disease (BM MRD) >0.01% in DS vs non-DS patients both at end of Induction (EOI; 54.1% vs 34.9%, p <0.0001) and at end of consolidation (EOC; 23.9% vs 12.0%, p=0.001). DS HR patients were also less likely to have favorable or unfavorable cytogenetics (p <0.0001). In terms of tolerability of the modified IM-1 phase, the duration was significantly longer in DS vs non-DS patients (mean 80.0 ± 16.6 days vs 74.0 ± 14 days, p <0.0001), and delays over 14 days were significantly more frequent (9.7% vs 4.7%, p=0.001). Nevertheless severe toxicities during IM-1 were low, with only 2 DS HR cases of grade 4 mucositis, 2 grade 4 infections, and 1 grade 5 event (sudden death, not otherwise specified). AALL1131 successfully achieved an induction death rate <10% in DS HR patients, although the rate remained significantly higher than in non-DS patients (3.6% vs 1.7%, p=0.035). Event-free survival (EFS) and overall survival (OS) in DS HR patients were improved compared to outcomes on older trials but remained significantly lower than non-DS patients (Figure 1), with 5-year EFS 69.1 ± 3.1% vs 79.5 ± 0.6% (p <0.0001), and 5-year OS 83.3 ± 2.5% vs 88.4 ± 0.5% (p=0.0005). Among DS HR patients, outcomes were particularly poor among those with EOC MRD >0.01% compared to those with EOC MRD <0.01% (5-year EFS 25.8 + 9.9% vs 62.2 + 6.6%, p <0.0021; 5-year OS 54.0 + 12.2% vs 88.1 + 4.5%, p <0.0003).

Conclusion: AALL1131 achieved the goal of decreasing induction mortality for DS HR patients, and the modified IM-1 phase utilizing ID MTX with early leucovorin rescue was well-tolerated, with minimal grade 4-5 toxicities, despite a longer mean duration and more frequent treatment delays compared to non-DS patients receiving HD MTX. DS HR patients continued to demonstrate disparities in EOI and EOC MRD levels, as well as in 5-year EFS and OS. Innovative strategies utilizing targeted therapies and immunotherapy are needed to further improve outcomes for patients with DS HR ALL.

Disclosures: Wood: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional Laboratory Services Agreement; Kite: Other: Institutional Laboratory Services Agreement; Novartis: Other: Institutional Laboratory Services Agreement; Beckman-Coulter: Honoraria; Becton-Dickinson: Honoraria; Beam: Other: Institutional Laboratory Services Agreement; Wugen: Other: Institutional Laboratory Services Agreement; Macrogenics: Other: Institutional Laboratory Services Agreement; Biosight: Other: Institutional Laboratory Services Agreement. Raetz: Pfizer: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Hunger: Amgen: Current equity holder in publicly-traded company, Honoraria; Jazz: Honoraria; Servier: Honoraria; Novartis: Consultancy.

*signifies non-member of ASH