Pediatric Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia Harboring Heterogeneous Genomic Profiles Respond to Venetoclax in Combination with Chemotherapy
Authors: Place Andrew E. , Karol Seth E. , Forlenza Christopher J. , Gambart Marion , Cooper Todd M. , Fraser Christopher , Cario Gunnar , O'Brien Maureen M , Gerber Nicolas U. , Barnette Phillip , Reinhardt Dirk , Ramsingh Giridharan , Tong Bo , Unnebrink Kristina , Vishwamitra Deeksha , Dunbar Fengjiao , Prine Betty A. , Palenski Tammy L. , Loh Mignon L. 
Published: February 2021

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 &lt;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 &lt;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.