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2793 Pediatric Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia Harboring Heterogeneous Genomic Profiles Respond to Venetoclax in Combination with Chemotherapy

Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Poster III
Hematology Disease Topics & Pathways:
Leukemia, ALL, Diseases, Pediatric, Lymphoid Malignancies, Study Population
Monday, December 7, 2020, 7:00 AM-3:30 PM

Andrew E. Place, MD, PhD1, Seth E. Karol, MD2, Christopher J. Forlenza, MD3*, Marion Gambart, MD4*, Todd M. Cooper, DO5, Christopher Fraser, MBBS6*, Gunnar Cario, MD, PhD7*, Maureen M O'Brien, MD8, Nicolas U. Gerber, MD9*, Phillip Barnette, MD10*, Dirk Reinhardt, MD PhD11, Giridharan Ramsingh, MD12*, Bo Tong, PhD13*, Kristina Unnebrink, PhD14*, Deeksha Vishwamitra, PhD13*, Fengjiao Dunbar, PhD13*, Betty A. Prine, BS13*, Tammy L. Palenski, PhD13 and Mignon L. Loh, MD15

1Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA
2Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN
3Memorial Sloan Kettering Cancer Center, New York, NY
4CHU de Toulouse, Toulouse, France
5Seattle Children’s Hospital, Cancer and Blood Disorders Center, Seattle, WA
6Queensland Children's Hospital, South Brisbane, QLD, Australia
7Universitätsklinikum Schleswig-Holstein, Kiel, Germany
8Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH
9University Children's Hospital Zurich, Zurich, Switzerland
10Primary Children's Hospital, Salt Lake City, UT
11University of Duisburg-Essen, Essen, Germany
12Genentech, Inc., South San Francisco, CA
13AbbVie Inc., North Chicago, IL
14AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany
15UCSF Benioff Children’s Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA

Introduction: Venetoclax (VEN) is an orally administered selective inhibitor of the B-cell lymphoma 2 (BCL2) antiapoptotic protein. VEN combined with chemotherapy (CTx) has demonstrated encouraging responses in a variety of hematologic malignancies. Here, we present safety, efficacy, and preliminary genomics results from our phase 1 study of VEN administered with CTx in pediatric patients (pts) with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL).

Methods: This open-label, phase 1, 2-part study enrolled pts <25 years old with different tumors including ALL (NCT03236857). In part 1, 5 pts with ALL received a weight- or age-adjusted adult-equivalent dose (AED) of 800 mg VEN PO daily after a 3-day ramp-up to mitigate tumor lysis syndrome risk; CTx could be added after 21 days of monotherapy (monoTx). In part 2, 20 pts with ALL received 800 mg AED VEN daily with CTx on day 4 following the ramp-up. Primary and secondary endpoints of the study included safety of VEN monoTx and preliminary efficacy of VEN ± CTx, respectively. Exploratory objectives included analysis of predictive biomarkers and minimal residual disease (MRD). Whole exome sequencing analysis was performed on baseline blood or bone marrow samples; gene fusion data were acquired through site-reported cytogenetic entries at screening. Highly recurrent genetic alterations in pediatric ALL were analyzed across a range of functional classifications. RNA sequencing analysis was performed on pretreated blood or bone marrow samples to evaluate gene expression of BCL2 family members.

Results: As of June 2020, 25 pts with ALL were enrolled and received VEN + CTx; CTx regimens included dexamethasone and/or vincristine and/or peg-asparaginase (D/V/P, n=16) or cytarabine and/or etoposide and/or peg-asparaginase (C, n=9). Pts had a median of 3.5 (range 1.0–9.0) prior therapies; the median duration of VEN therapy was 2.1 mo (range 0.4–4.6). Most common reasons for VEN discontinuation were progressive disease (28%; D/V/P: n=1; C: n=6) or continuation to transplant (28%; D/V/P: n=6; C: n=1). Eight (32%; D/V/P: n=4; C: n=4) pts had fatal adverse events (AEs), all unrelated to VEN. Most common grade 3/4 AEs were febrile neutropenia (52%) and anemia (44%); 1 pt (D/V/P)completed ramp up, but reported laboratory tumor lysis syndrome with CTx combination.

A best objective response rate (ORR) of 56% was seen with VEN + D/V/P: 4 complete responses (CR), 4 CR with incomplete marrow recovery (CRi), and 1 CR without platelet recovery (CRp). ORR of 11% (CRi: n=1) was seen with VEN + C (Table). In pts who achieved CR/CRi/CRp, MRD <10−4 leukemic cells were observed in 28% of all pts (VEN + D/V/P: n=6; VEN + C: n=1).

Genetic analysis of evaluable pts (VEN + D/V/P: n=12; VEN + C: n=6) demonstrated a highly heterogeneous genomic landscape (Figure A) including a range of somatic mutations and structural variants, comprising translocations, rearrangements, and chromosomal abnormalities. Analysis of mutations found in ≥2 pts revealed that responses were seen in VEN + D/V/P-treated pts with CREBBP, KMT2A, KMT2D, RB1, PTPN11, and PDGFRB mutations. Of the pts who had CREBBP mutations, 2/3 obtained CR. Pts with mutations in RB1, PTPN11, and PDGFRB (n=2 each) also achieved CR or CRi. Of the pts with KMT2A or KMT2D mutations detected by our sequencing platform, 1/2 and 2/4 achieved CR, respectively. Furthermore, of the 6 pts with KMT2A translocations identified locally, 3 obtained CR with VEN + D/V/P. Baseline gene expression profiling revealed that BCL-xL and MCL1 levels were slightly higher in comparison to BCL-2 (Figure B). There was no significant correlation between these gene expression levels and response. No mutations were detected in BCL2, BCL-xL, or MCL1.

Conclusions: VEN + CTx was well tolerated, with no unexpected toxicities in pediatric pts with R/R ALL. Promising preliminary efficacy was observed in these refractory pts receiving VEN + D/V/P (ORR 56%). Our genomic profiling suggests that responses with VEN + CTx occur in pediatric ALL with a variety of mutations, including those with KMT2A rearrangements. However, due to the limited sample size and the overall heterogeneity, further investigation in a larger pt cohort is warranted to determine which mutations confer resistance or sensitivity to VEN.

Disclosures: Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Karol: AbbVie: Other: Unrelated to this study, St. Jude has received a charitable contribution from AbbVie, Inc. The charitable contribution is not being used for clinical or research activities, including any activities related to this study. . Gambart: Jazz Pharmaceuticals: Other: travel, accommodations, expenses; Eisai: Other: travel, accommodations, expenses. Cooper: Celgene: Other: Spouse was an employee of Celgene (through August 2019). Fraser: Novartis, Amgen: Consultancy. Cario: Jazz Pharmaceuticals: Consultancy, Other: travel support; Novartis: Consultancy, Other: travel support. O'Brien: Celgene: Research Funding; Jazz: Research Funding; Amgen: Research Funding; BMS: Research Funding; AbbVie: Research Funding; Pfizer: Honoraria, Research Funding; Incyte: Research Funding. Gerber: AbbVie, Loxo, Novartis: Other: Institutional Research Funding. Reinhardt: Behring: Other: Institutional Research Funding; Novo Nordisk: Other: Institutional Research Funding; Biotest: Other: Institutional Research Funding; Roche: Consultancy, Other: Institutional Research Funding; bluebird bio: Consultancy; Celgene: Consultancy, Other: Institutional Research Funding; Jazz: Consultancy, Other: Institutional Research Funding; Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Ramsingh: Genentech: Current Employment, Current equity holder in publicly-traded company; Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Tong: AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Unnebrink: AbbVie: Current Employment, Other: may hold stock or other options. Vishwamitra: AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Dunbar: Abbvie: Current Employment, Current equity holder in publicly-traded company. Prine: AbbVie: Current Employment, Other: may hold stock or other options. Palenski: AbbVie: Current Employment, Other: may hold stock or other options. Loh: Pfizer: Other: Institutional Research Funding; Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA approved for some indications. Venetoclax for treatment of pediatric ALL is not an approved indication.

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