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2949 Treatment Intensification Does Not Improve Outcome for Children with Myeloid Leukemia of Down Syndrome (ML-DS) Who Are MRD-Positive after Induction Therapy: A Report from the Children’s Oncology Group

Program: Oral and Poster Abstracts
Session: 619. Acute Myeloid Leukemias: Disease Burden and Minimal Residual Disease in Prognosis and Treatment: Poster II
Hematology Disease Topics & Pathways:
Combination therapy, Pediatric, Treatment Considerations, Adverse Events, Study Population, Human, Measurable Residual Disease
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Johann K. Hitzler, MD1, Todd A. Alonzo, PhD2*, Robert Gerbing, MS3*, Jim Wang, MS2*, Amy Beckman, MD4*, Betsy Hirsch, PhD5*, Susana C. Raimondi, PhD6*, Karen M Chisholm, MD, PhD7, Shelton A. Viola, MD8*, Anupam Verma, MD9*, Lisa Eidenschink Brodersen, PhD10*, Michael R. Loken, PhD11*, Jeffrey W. Taub, MD12, Alan S Gamis, MD, MPH13, E. Anders Kolb, MD14, Todd M Cooper, DO15 and Jason N. Berman, MD16

1Division Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, CAN
2Children's Oncology Group, Monrovia, CA
3Children's Oncology Group, Arcadia, CA
4Division of Laboratory Medicine, University of Minnesota, Minneapolis, MN
5University of Minnesota, Minneapolis, MN
6St. Jude Children's Rsch. Hosp., Memphis, TN
7University of Washington, Seattle, WA
8Naval Medical Center- Portsmouth, Portsmouth, VA
9Inova Fairfax Hospital, Fairfax, VA
10Children's Hospital of Philadelphia, Philadelphia, PA
11Hematologics, Inc., Seattle, WA
12Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI
13Hematology/Oncology/BMT, Children's Mercy Kansas City, Kansas City, MO
14Leukemia & Lymphoma Society, Bronx, NY
15Division of Pediatric Hematology, Oncology, Bone Marrow Transplant & Cellular Therapy, Seattle Childrens Hospital, Seattle, WA
16CHEO Research Institute, Ottawa, ON, CAN

Background. Myeloid leukemia of Down syndrome (ML-DS) is a distinct form of pediatric AML that is treated with DS-specific reduced intensity chemotherapy with a resulting favorable prognosis (5-year EFS 89.9%). In contrast, non-responders and patients with relapsed ML-DS have a dismal outcome. The aim of Children’s Oncology Group (COG) study AAML1531 was introduce risk stratification of chemotherapy intensity for patients with ML-DS based on measurable residual disease by multi-parameter flow cytometry at the end of the first course of induction (EOI-1 MRD), which is used to risk stratify treatment intensity for non-DS pediatric AML patients and was prognostic in the preceding ML-DS trial, AAML0431.

Methods. AAML1531 enrolled 280 patients with ML-DS between November 2015 and April 2022. All patients received the same first course of induction therapy (Induction I): daunorubicin, cytarabine, 6-thioguanine (DAT). Those with EOI-1 MRD <0.05% were classified as Standard Risk (SR, Arm A) and treated with reduced-intensity chemotherapy based on the historical control, AAML0431, but with elimination of the second induction course of AAML0431 therapy, which consisted of high-dose cytarabine/asparaginase, to reduce infectious events. Patients with EOI-1 MRD >0.05% were classified as High Risk (HR, Arm B) and had their subsequent treatment intensified to a level consistent with that of pediatric non-DS AML (Induction II: mitoxantrone/high-dose cytarabine; Intensification I: cytarabine/etoposide; Intensification II: high-dose cytarabine/asparaginase) with the aim of reducing the number of relapse events. Cytogenetic results were centrally reviewed and MRD was measured by multidimensional flow cytometry in a reference laboratory (Hematologics, Inc., Seattle, WA).

Results. We previously reported outcomes for the SR group (n=114) (Hitzler et al. Blood 2021). We now report outcomes of patients in the ML-DS HR group (n=41). Efficacy: Intensification of chemotherapy for EOI-1 MRD-positive patients did not significantly improve the 2-year EFS compared to that of the AAML0431 EOI-1 MRD-positive cohort (AAML1531: 80.5 + 12.4% vs. AAML0431: 76%, p=0.247). OS also did not differ significantly (AAML1531: 80.5 + 12.4% vs. AAML0431: 76.2 + 18.6%, p=0.819). There were 7 relapses and 1 death as first event. Of the 7 patients with relapse, 6 did not survive (2-year-OS 14.3 + 26.5% after relapse). Adverse events: Febrile neutropenia (FN) occurred in 25.4% of all AAML1531 patients during the common Induction I phase. During intensified post-induction therapy on the HR arm, the course-specific proportions of FN were 31.7% of 41 patients (Induction II), 27.5% of 40 patients (Intensification I) and 26.3% of 38 patients (Intensification II). The corresponding proportions on the reduced-intensity SR arm were significantly lower than on the HR arm: 3.7% of 108 patients (Induction II, p<0.001), 6.9% of 101 patients (Induction III, no corresponding HR course), 6.1% of 98 patients (Intensification I, p=0.001) and 8.6% of 93 patients (Intensification II, p=0.008). Sepsis grade 3 or greater was reported in 9.8% of 41 patients (Induction II, p=0.005) treated on HR arm compared to none treated on the SR (Ind II, n=108), and in 3.3% in the common Induction phase (Induction I).

Conclusions. Intensification of chemotherapy for patients with ML-DS with positive EOI-1 MRD neither improved EFS nor OS and resulted in more FN and a greater number of sepsis events. While EOI-1 flow cytometric MRD detected ML-DS patients whose outcomes were poorer than those without MRD (Taub et al. Blood 2017), intensification of chemotherapy was not beneficial to the MRD-positive group. Overall, results of AAML1531 demonstrate that stratification of treatment intensity according to flow cytometric EOI-1 MRD did not did not improve outcomes for patients with ML-DS. Alternative approaches such as mutational profiling of ML-DS blasts should be evaluated with regard to prognostication, risk stratification and identification of targets for novel agents to improve the overall outcome for this disease.

Disclosures: Loken: Hematologics: Current Employment. Berman: Oxford Immune Algorithimics: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH