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2725 A Phase 2 Study of Ruxolitinib with Chemotherapy in Children with Philadelphia Chromosome-like Acute Lymphoblastic Leukemia (AALL1521/INCB18424-269): Biologic Characteristics and Minimal Residual Disease Response of Patients with Non-CRLF2-Rearranged JAK Pathway AlterationsClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Lymphoid Leukemias, ALL, Clinical Research, Combination therapy, pediatric, Diseases, Therapies, young adult , Lymphoid Malignancies, Study Population, Human, Minimal Residual Disease
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Sarah K Tasian, MD1,2, Deborah S Hunter, PhD3*, I-Ming L Chen4, Richard C Harvey, PhD4, Andrew J. Carroll, PhD5, Elizabeth Wagner6*, Shalini C Reshmi, PhD6, Michael J Borowitz, MD PhD7, Brent L. Wood, MD PhD8, Jeannie Daniel, PhD3*, Meenakshi Devidas, PhD, MBA9, Elizabeth A. Raetz, MD10, Stephen P. Hunger, MD11, Albert Assad, MD3* and Mignon L. Loh, MD12

1Department of Pediatrics and Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
2Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA
3Incyte Corporation, Wilmington, DE
4University of New Mexico Cancer Center, Albuquerque, NM
5Department of Genetics, University of Alabama at Birmingham, Birmingham, AL
6Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH
7Departments of Pathology and Oncology, Johns Hopkins Hospital, Baltimore, MD
8Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA
9Department of Global Pediatric Medicine, St Jude Children's Research Hospital, Memphis, TN
10Division of Pediatric Hematology and Oncology, Stephen D. Hassenfeld Children's Center for Cancer and Blood Disorders, NYU Langone Health, New York, NY
11Department of Pediatrics and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia and the Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA
12Division of Hematology, Oncology, BMT, and Cellular Therapies, Seattle Children's Hospital, Seattle, WA

Background: Children and adolescents/young adults (AYAs) with NCI high-risk Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) experience high relapse rates and poor clinical outcomes with conventional chemotherapy. Approximately 70% of Ph-like ALL is driven by oncogenic kinase fusions or mutations that induce constitutive JAK/STAT signaling, including CRLF2 rearrangements with frequent JAK2 co-mutations, JAK2 rearrangements, EPOR rearrangements, SH2B3 deletions, and IL7R indels. The Part 2/efficacy phase of the Children’s Oncology Group (COG) AALL1521/INCB18424-269 phase 2 trial (NCT02723994) is testing the hypothesis that addition of the selective JAK1/2 inhibitor ruxolitinib to the standard of care high-risk B-ALL chemotherapy backbone will improve 3-year event-free survival (EFS) of children and AYAs with the most common CRLF2-rearranged (R) subtype of Ph-like ALL (n=84 patients; Cohorts A and B). After exploration of 6 dose levels, the recommended phase 2 dose of ruxolitinib in combination with chemotherapy was identified as 50 mg/m2/dose x 14 days on/14 days off per cycle in the Part 1/safety phase of AALL1521 conducted in 40 pediatric patients (Tasian ASH 2018 #555). We now report the biologic characteristics of patients with non-CRLF2-rearranged Ph-like ALL enrolled in the descriptive Cohort C of AALL1521 and their early treatment responses by minimal residual disease (MRD) assessment.

Methods: Children and AYAs aged 1-21 years with Ph-like ALL and eligible JAK pathway genetic alterations in Cohort C were enrolled in Part 1 (September 2016 to August 2018) or Part 2 (August 2018 to August 2019) for treatment with ruxolitinib and post-induction chemotherapy. Genetic characterization of diagnostic bone marrow or peripheral blood ALL specimens was performed via 8-gene low-density microarray (LDA) profiling for the Ph-like gene expression signature, fluorescence in situ hybridization, RNA-based kinase fusion analysis, and/or DNA-based next generation sequencing in COG reference laboratories as described (Harvey & Tasian Blood Adv 2020). End of induction (EOI) and end of consolidation (EOC) MRD assessment was performed via flow cytometry analysis with positive MRD defined at 0.01%.

Results: Within Cohort C, 5 patients with non-CRLF2-R Ph-like ALL were enrolled in Part 1 and 18 patients in Part 2. The mean age and diagnostic white blood cell counts were 13.3 years and 145,700/μL blood, respectively. Fifteen patients had JAK2 fusions (with 3’ partners EBF1, HAUS6, HOOK3, PAX5, SNX29, SSBP2, or TERF2), 5 had EPOR rearrangements (with 3’ partners IGH or MTRNR2L8), and 3 had IL7R indels. Ph-like LDA scores were uniformly high in Cohort C cases with a mean value of 0.826 (Figure 1A). High EPOR expression level (DCt <4) on LDA was predictive of true EPOR rearrangement identified on fusion analysis. All Cohort C patients had residual disease after 4-drug induction chemotherapy (without ruxolitinib) with mean EOI MRD 10.7% (range 0.01-49%). Two of 5 patients (40%) in Parts 1 and 8/18 patients (44.4%) in Part 2 achieved EOC MRD negativity (Figure 1B). Two Part 1 and 9 Part 2 patients (including two patients with EOC MRD+ at 0.04% or 0.1%) continued post-consolidation chemotherapy with ruxolitinib with several patients now status post therapy completion. One additional Part 2 Cohort C patient with a JAK2 fusion and negative EOC MRD proceeded to elective hematopoietic stem cell transplantation in first remission outside of the AALL1521 trial.

Conclusions: Patients with Ph-like ALL harboring JAK2 or EPOR rearrangements or IL7R indels routinely had higher LDA scores and levels of EOI MRD positivity versus those with the more common CRLF2-R subtype (Tasian ASH 2020 #1095). JAK2 rearrangements occurred most frequently amongst Cohort C patients, often with previously-unknown gene partners. Although 13/23 (56.5%) of Cohort C patients were EOC MRD+, most patients demonstrated a marked decrement in EOI to EOC MRD with ruxolitinib and consolidation chemotherapy. The optimal duration of JAK inhibitor therapy and potential response rates in patients with Ph-like ALL remain undefined. Future analyses of MRD levels and 3-year EFS in patients with CRLF2-R +/- JAK-mutant Ph-like ALL enrolled in Cohorts A and B of the AALL1521 trial will help to ascertain potential outcomes benefit of ruxolitinib addition to chemotherapy, although responses may differ from those of Cohort C patients.

Disclosures: Tasian: GSK: Consultancy; Aleta Biotherapeutics: Consultancy; Beam Therapeutics: Research Funding; bluebird bio: Consultancy; Syndax Pharmaceuticals: Consultancy; Kura Oncology: Consultancy, Research Funding; Incyte Corporation: Research Funding. Hunter: Incyte Corporation: Current Employment. Daniel: Incyte Corporation: Current Employment, Current equity holder in private company. Raetz: BMS: Other: Data and Safety Monitoring Board; Pfizer: Research Funding. Hunger: Servier: Honoraria; Jazz: Honoraria; Amgen: Current equity holder in private company, Honoraria. Assad: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company.

OffLabel Disclosure: This clinical trial is investigating the therapeutic potential of the JAK inhibitor ruxolitinib in combination with multi-agent chemotherapy for children, adolescents, and young adults with Ph-like ALL.

*signifies non-member of ASH