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1094 Outcomes of Patients with Down Syndrome and CRLF2-Overexpressing Acute Lymphoblastic Leukemia (ALL): A Report from the Children’s Oncology Group (COG)

Program: Oral and Poster Abstracts
Session: 618. Acute Lymphoblastic Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster I
Hematology Disease Topics & Pathways:
Leukemia, ALL, Diseases, Lymphoid Malignancies
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Karen R Rabin, MD, PhD1,2, Meenakshi Devidas, PhD3*, Zhiguo Chen4*, Yunfeng Dai, PhD5*, Sarah K Tasian, MD6, Johann K Hitzler, MD7, Kathryn G Roberts, PhD8, Andrew J Carroll, PhD9, Nyla A Heerema, PhD10, Michael J Borowitz, MD, PhD11, Brent L Wood, MD, PhD12, Charles G Mullighan, MBBS, MD8, Richard C Harvey, PhD13, I-Ming L Chen14, Cheryl L Willman, MD15, Shalini C Reshmi, PhD16, Julie M Gastier-Foster, PhD17, Kelly W Maloney, MD18, Eric C Larsen, MD19*, Reuven J Schore, MD20, Michael J Burke, MD21, Wanda L Salzer, MD22, Naomi J Winick, MD23, William L. Carroll, MD24, Elizabeth A. Raetz, MD25, Anne Angiolillo, MD26*, Mignon L. Loh, MD27 and Stephen P Hunger, MD28

1Baylor College of Medicine TX Children's Cancer Center, Houston, TX
2Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
3Global Pediatric Medicine, St Jude Children's Research Hospital, Memphis, TN
4Department of Biostatistics, Colleges of Medicine, Public Health, and Health Professions, University of Florida, Gainesville, FL
5Department of Biostatistics, University of Florida, Gainesville, FL
6Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA
7The Hospital for Sick Children, Toronto, ON, Canada
8Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
9Department of Genetics, University of Alabama at Birmingham, Birmingham, AL
10Department of Pathology, The Ohio State University, Columbus, OH
11Departments of Pathology and Oncology, Johns Hopkins University, Baltimore, MD
12Department of Laboratory Medicine, University of Washington, Seattle, WA
13University of New Mexico School of Medicine, Albuquerque, NM
14Department of Pathology, University of New Mexico Cancer Research Facility, Albuquerque, NM
15Department of Pathology, University of New Mexico Comprehensive Cancer Center, Albuquerque, NM
16Nationwide Children's Hospital, Columbus, OH
17Department of Pediatrics, Section of Hematology/Oncology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX
18Department of Pediatrics, Division of Pediatric Hematology/Oncology/BMT, Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora, CO
19Department of Pediatrics, Maine Children's Cancer Program, Scarborough, ME
20Children's National Medical Center, Washington, DC
21Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI
22U.S. Army Medical Research and Materiel Command, Olney, MD
23Department of Pediatrics, Division of Pediatric Hematology/Oncology, UT Southwestern, Simmons Cancer Center, and Perlmutter Cancer Center, Dallas, TX
24Division of Pediatric Hematology and Oncology, Perlmutter Cancer Center, NYU Cancer Institute, New York, NY
25Stephen D. Hassenfeld Children's Center for Cancer and Blood Disorders, New York, NY
26Chiildren's National Medical Center, Washington, DC
27Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of California Benioff Children’s Hospital, San Francisco, CA
28Department of Pediatrics, Division of Oncology and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

Background: Patients with Down syndrome (DS) have an approximately 10-fold increased risk of developing ALL, and the spectrum of genetic alterations differs from that of non-DS ALL. Rearrangement and/or overexpression of cytokine receptor-like factor 2 (CRLF2+) occurs in 50% of DS ALL, compared to only 5-10% CRLF2+ cases in non-DS children and adolescents. JAK2 or JAK1 mutations co-occur in about half of CRLF2+ cases in both DS and non-DS ALL. The prognostic significance of CRLF2+ ALL also appears to differ in the limited data reported to date, with less adverse impact in patients with DS compared to non-DS ALL. Here, we report the clinical characteristics and prognostic significance of B-ALL with CRLF2 overexpression and JAK alterations in children and adolescents/young adults (AYA) with DS who were treated on Children’s Oncology Group (COG) clinical trials from 2003-2016.

Methods: We analyzed clinical, laboratory, and outcome data for 317 patients with DS B-ALL treated on standard risk (SR) trials AALL0331 and AALL0932 and high risk (HR) trials AALL0232 and AALL1131, for whom CRLF2 status and rearrangement partners (IGH or P2RY8) were ascertained by flow cytometric assessment of surface expression; fluorescence in situ hybridization; and/or polymerase chain reaction (PCR) testing. JAK mutations were ascertained in a subset by PCR and sequencing. Minimal residual disease (MRD) was assessed by flow cytometry at the end of induction (EOI) and at end of consolidation (EOC) for a subset of EOI MRD+ patients.

Results: We identified 168/317 (53.0%) CRLF2+ cases, and among those assessed for CRLF2 partner, 17/73 (23.3%) were IGH-CRLF2 and 56/73 (76.7%) were P2RY8-CRLF2. In the subset of 165 cases tested for JAK mutations (85 CRLF2- and 80 CRLF2+), 42/165 (25.4%) had JAK mutations, all of which co-occurred in CRLF2+ cases. CRLF2 positivity was significantly associated with younger age at diagnosis: 140/168 (83.3%) of CRLF2+ cases were under 10 years old, versus 106/149 (71.1%) of CRLF2- cases, p<0.01. P2RY8-CRLF2 cases were significantly more likely than IGH-CRLF2 cases to be associated with age under 10 years at diagnosis (92.9% vs 29.4%, p<0.0001), initial white blood count (WBC) <50x103 (80.4% vs 52.9%, p<0.024), National Cancer Institute (NCI) standard risk status (73.2% vs 23.5%, p<0.0002), and day 29 MRD <0.01% (67.9% vs 37.5%, p<0.028). There were no significant associations between JAK mutation status and any clinical features assessed (sex, initial WBC, central nervous system or testicular involvement, NCI risk group, or EOI/EOC MRD). Among patients with neutral cytogenetics (defined as neither favorable [ETV6-RUNX1, double trisomies of chromosomes 4 and 10] nor unfavorable [BCR-ABL1, KMT2A-rearranged, hypodiploid, iAMP21]), survival did not significantly differ between CRLF2+ and CRLF2- patients (Figure 1A,B), either for 5-year event-free survival (EFS) (79.1 +3.6% vs 77.6 +4.7%, p=0.856) or 5-year overall survival (OS) (89.5 ±2.8% vs 84.9 ±4.1%, p=0.674). There were also no significant differences in EFS or OS based on JAK mutation status or CRLF2 partner, although there were trends toward poorer outcomes in the CRLF2+/JAK+ and IGH-CRLF2 subgroups (Figure 1C). Finally, there was no significant difference in 5-year cumulative incidence of relapse (CIR) according to CRLF2 status (CRLF2+ 16.0 +3.0%, CRLF2- 10.6 +2.6%, p=0.179), although there were non-significant trends toward more relapses in CRLF2+ cases overall and in the NCI HR subgroup analysis.

Discussion: Whereas CRLF2 and JAK alterations are associated with higher MRD, poorer survival, and increased CIR in patients with high-risk ALL without DS, these alterations do not demonstrate strong adverse prognostic impact in children and AYAs with DS-ALL treated on recent frontline COG trials, although larger sample sizes are needed to adequately assess for possible poorer prognoses associated with the CRLF2+/JAK+ and IGH-CRLF2 subgroups. Regardless, given the frequency of these targetable lesions and the increased risk of relapse and chemotherapy-associated toxicities in patients with DS-ALL, targeted therapies currently under investigation for these genetic lesions may be beneficial to replace some intensive blocks of therapy in DS-ALL with CRLF2 and/or JAK alterations, both to enhance anti-leukemic efficacy and decrease intensive chemotherapy-associated toxicities.

Disclosures: Tasian: Gilead Sciences: Research Funding; Incyte Corporation: Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees. Borowitz: Amgen: Honoraria. Mullighan: AbbVie, Inc.: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Illumina: Consultancy, Honoraria, Speakers Bureau. Raetz: Celgene: Other: DSMB member; Pfizer: Other: Institutional research funding. Loh: Pfizer: Other: Institutional Research Funding; Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hunger: Novartis: Consultancy; Amgen: Current equity holder in publicly-traded company, Honoraria.

*signifies non-member of ASH