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961 Feasibility and Outcome of Post-Induction Therapy Incorporating Dasatinib for Patients with Newly Diagnosed ABL-Class Fusion B-Lymphoblastic Leukemia (ABL-class Fusion B-ALL): Children’s Oncology Group AALL1131

Program: Oral and Poster Abstracts
Type: Oral
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Novel Therapies for ALL
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Research
Monday, December 11, 2023: 4:30 PM

Wanda L. Salzer, MD1, Michael J. Burke, MD2*, Meenakshi Devidas, PhD, MBA3, Zhiguo (Bruce) Chen, MS4*, Michael J. Borowitz, MD, PhD5, Andrew J Carroll, PhD6, I-Ming L. Chen, DVM, MS7, Julie M. Gastier-Foster, PhD8*, Richard C. Harvey, PhD9*, Nyla A. Heerema, PhD10*, Charles G. Mullighan, MBBS, MD11, Karen R. Rabin, MD, PhD12, Shalini C Reshmi, PhD13, Cheryl L. Willman, MD14*, Brent L. Wood, MD, PhD15, Naomi J. Winick, MD16, William L. Carroll, MD17, Elizabeth A. Raetz, MD18, Mignon L. Loh, MD19 and Stephen P. Hunger, MD20

1Uniformed Services University, Bethesda, MD
2The Medical College of Wisconsin Inc, Milwaukee, WI
3St Jude Children's Research Hospital, Memphis, TN
4Biostatistics, University of Florida, Gainesville, FL
5Johns Hopkins University School of Medicine, Baltimore, MD
6Department of Genetics, University of Alabama at Birmingham, Birmingham, AL
7University of New Mexico Cancer Rsch Facility, Albuquerque, NM
8Nationwide Childrens Hospital Ohio State University, Houston, TX
9University of New Mexico School of Medicine, Albuquerque, NM
10Ohio State University, Columbus, OH
11Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
12Department of Pediatrics, Baylor College of Medicine, Baylor College of Medicine TX Children's Cancer Center, Houston, TX
13Nationwide Children's Hospital, Columbus, OH
14Mayo Clinic, Rochester, MN
15Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA
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
18Department of Pediatrics, NYU Langone Health, New York, NY
19Ben Towne Center for Childhood Cancer Research, Seattle Children’s Hospital, Seattle, WA
20Childrens Hospital of Philadelphia, Philadelphia

Background: Approximately 2-3% of B-ALL patients have Philadelphia chromosome like (Ph-like) B-ALL with an ABL-class fusion (ABL1, ABL2, PDGFRB, or CSF1R fusions), but lacking BCR::ABL1. These patients are predicted to be sensitive to ABL-class tyrosine kinase inhibitors, such as imatinib or dasatinib. Ph-like B-ALL is associated with male sex, older age, higher initial white blood cell (WBC) count, elevated end of induction (EOI) minimal residual disease (MRD), and poor outcome. The AALL1131 Dasatinib arm was designed to evaluate response to therapy following induction of patients with ABL-class fusion B-ALL, when given dasatinib continuously on a modified Berlin-Frankfurt-Münster (MBFM) backbone.

Methods: Between February 2012 and March 2019, AALL1131 enrolled patients 1-30 years with newly diagnosed high risk (HR) B-ALL. AALL1131 was amended in August 2016, to include the Dasatinib arm for patients with ABL-class fusions involving ABL1, ABL2, PDGFRB, and CSF1R. Patients with Down Syndrome were not eligible for the Dasatinib arm. ABL-class fusion B-ALL patients with a predicted TKI-sensitive mutation were screened by low density array (LDA) PCR and confirmed by additional molecular testing. Following 4-drug induction, patients with HR B-ALL and ABL-class fusions received MBFM with dasatinib (60 mg/m2, maximum 140 mg) daily from start of consolidation through end of maintenance. Dasatinib was held only for toxicity.

Results: Twenty-two evaluable patients with HR B-ALL were non-randomly assigned to the Dasatinib arm. ABL-class 3’ partners included ABL1 (n=4), ABL2 (n=4), PDGFRB (n=12), and CSF1R (n=2). Compared to all patients on AALL1131, patients treated on the Dasatinib arm were older (median age at diagnosis 14 versus 10 years, p=0.008), more often male (77% versus 56%, p=0.046), and had a trend towards an increased initial WBC (median WBC at diagnosis 44,000/µL versus 19,000/µL, p=0.086). Patients with ABL-class fusions had EOI MRD > 0.01% in 20 of 22 patients and available end of consolidation MRD >0.01% in 6 of 10 patients. Only 5 of 22 (22.7%) patients completed prescribed protocol therapy. Reasons for therapy discontinuation included induction failure (n=2), relapse (n=1), alternate therapy (n=1), determined to be in the patient’s best interest (n=10), death (n=1), unknown (n=2). Compared to all patients on AALL1131, four-year disease-free survival was 52.5+18.1% versus 86.8+0.7% (p<0.0001) and overall survival 79.4+13.6% versus 89.2+0.4% (p<0.0001). Dasatinib was well tolerated with no unexpected treatment related toxicities.

Conclusion: Patients with ABL-class fusions were more likely male, EOI MRD+, and had poorer outcomes. Seventy-seven percent of patients enrolled on the Dasatinib arm did not complete prescribed therapy. While dasatinib was well tolerated, treatment failures occurred early, indicating alternate strategies are needed.

Disclosures: Mullighan: Pfizer: Research Funding; Abbvie: Research Funding; Amgen: Honoraria; Illumina: Honoraria. 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: Bristol Myer Squibb: Other: DSMC; Pfizer: Research Funding. Hunger: Jazz: Honoraria; Amgen: Current equity holder in publicly-traded company, Honoraria; Novartis: Consultancy; Servier: Honoraria.

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