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709 Efficacy Findings in a Phase 3, Randomized Trial of Eltrombopag Vs. Standard First-Line Treatment for Newly Diagnosed Immune Thrombocytopenia in Children

Program: Oral and Poster Abstracts
Type: Oral
Session: 311. Disorders of Platelet Number or Function: Clinical and Epidemiological: Clinical Evidence in ITP
Hematology Disease Topics & Pathways:
Research, Clinical trials, Bleeding and Clotting, Clinical Research, Pediatric, Thrombocytopenias, Diseases, Human, Study Population
Monday, December 9, 2024: 10:30 AM

Kristin A. Shimano, MD1, Amanda B. Grimes, MD2,3, Melissa J Rose, DO4, Shipra Kaicker, MD5, Sanjay J. Shah, MBBS6,7, Michael Briones, DO8*, Elizabeth Gunn, MD9, Taizo A. Nakano, MD10, Jeffrey D Lebensburger, DO11, Michele P. Lambert, MD12,13, Stephanie A. Fritch Lilla, MD14, Rohith Jesudas, MBBS15, Cathy A. Lee-Miller, MD16*, Alexis Thompson, MD, MPH17,18, Rukhmi Bhat, MD, MS19, Stacey Rifkin-Zenenberg, DO20, Suvankar Majumdar, MBBChir21*, Manpreet Kochhar, MD, MS22*, Shelley E Crary, MD, MS23, Kerry Hege, MD24, Jennifer A. Rothman, MD25, James B. Ford, DO26, Joshua J Bies, MD27*, John Fort, MD28*, Loan Hsieh, MD29, Maritza E. Ruiz, MD30, Kathryn M. Carrier31,32*, Bogdan Dinu2*, Julia MW Wong, PhD, RD33,34,35*, Pei-Chi Kao36,37*, Wendy B. London, PhD36,38*, Staci D. Arnold, MD, MBA, MPH39*, Carolyn M. Bennett, MD, MSc40, Jenny Despotovic, DO41*, Robert J. Klaassen, MD, FRCPC42, Ellis J. Neufeld, MD15, Cindy E Neunert, MD43,44 and Rachael F. Grace, MD, MMSc45

1Pediatric Allergy, Immunology, and Bone Marrow Transplant Division, University of California San Francisco Benioff Children's Hospital, San Francisco, CA
2Texas Children’s Cancer and Hematology Center, Houston, TX
3Baylor College of Medicine, Houston, TX
4Division of Pediatric Hematology & Oncology, Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University, Columbus, OH
5Department of Pediatric Hematology Oncology, Weill Cornell Medicine/New York Presbyterian-Weill Cornell Medical College, New York, NY
6Department of Child Health, Phoenix Children’s Hospital, University of Arizona College of Medicine, Chandler, AZ
7Phoenix Children's Hospital, Center for Cancer and Blood Disorders, Phoenix, AZ
8Children's Hospital of Atlanta, Atlanta, GA
9Aflac Cancer and Blood Disorders Center at Children's Healthcare of Atlanta, Emory University, Atlanta, GA
10Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO
11University of Alabama at Birmingham, Birmingham, AL
12Children's Hospital of Philadelphia, Philadelphia, PA
13Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
14Children's Minnesota, Minneapolis, MN
15St. Jude Children's Research Hospital, Memphis, TN
16University of Wisconsin School of Medicine and Public Health, American Family Children’s Hospital, Madison, WI
17Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
18Division of Hematology, Children’s Hospital of Philadelphia, Phildelphia, PA
19Northwestern University Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
20Pediatric Hematology/Oncology Division, Hackensack Meridian Health, Hackensack, NJ
21Children's National Medical Center, Washington, DC
22The Warren Alpert Medical School at Brown University, Hasbro Children's Hospital, Providence, RI
23Pediatric Hematology/Oncology, University of Arkansas for Medical Sciences, Little Rock, AR
24Riley Children's Health, Indiana University School of Medicine, Indianapolis, IN
25Duke University Medical Center, Durham, NC
26Primary Children's, Salt Lake City, UT
27University of Nebraska Medical Center, Omaha, NE
28Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Florida College of Medicine, Gainesville, FL
29Children's Hospital, Orange County, Orange, CA
30CHOC Children's, Orange, CA
31Harvard Medical School, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA
32Boston Children’s Hospital, Boston, MA
33Harvard Medical School, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Brookline, MA
34Broad Institute of MIT and Harvard, Boston
35Boston Children’s Hospital, Boston
36Boston Children's Hospital, Boston, MA
37Dana-Farber Cancer Institute, Boston, MA
38Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA
39Aflac Canver and Blood Disorders Center at Children's Healthcare of Atlanta, Emory University, Atlanta
40Spark Therapeutics, Philadelphia, PA
41Agios Pharmaceuticals, Inc., Cambridge, MA
42Division of Hematology/Oncology, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada
43Morgan Stanley Children's Hospital, New York, NY
44Columbia University Irving Medical Center, New York, NY
45Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA

Background: First-line treatments for patients (pts) with newly diagnosed immune thrombocytopenia (ITP) include corticosteroids, intravenous immunoglobulin (IVIg), and anti-D globulin. Eltrombopag (epag), a thrombopoietin receptor agonist, was FDA approved for children with chronic ITP in 2015. The efficacy of epag in the newly diagnosed phase of pediatric ITP is unknown.

Methods: The Pediatric ITP Newly diagnosed pts Epag vs Standard therapy (PINES) trial, NCT03939637, is an investigator-initiated, prospective, open label, randomized, multi-center trial sponsored by the ITP Consortium of North America (ICON) and funded by Novartis. Pts ages 1-<18 with primary ITP, ≤3 months from diagnosis, with platelet count <30 x109/L who required pharmacologic treatment per the treating clinician were randomized 2:1, stratified by age and prior treatment status, to receive the experimental treatment, epag, or investigator's choice of one of 3 standard first-line therapies (SOC): prednisone, IVIg, or anti-D globulin at specified doses. The primary endpoint of ‘response’ was ≥3 of 4 platelet counts >50 x109/L during weeks 6-12 without rescue treatment. This intent-to-treat analysis includes data from all randomized pts for the first 12 weeks of the study. Secondary endpoint analyses include data from all evaluable pts who received at least 1 dose of assigned treatment. The WHO Bleeding Scale and Modified Buchanan Scale (MBS) were used to assess bleeding severity. The parent-proxy reported KIDS ITP Tool (KIT) scores were used to measure health-related quality-of-life (QoL). A one-sided z-test, at alpha=0.025, tested the superiority of epag vs SOC for the primary endpoint. Two planned interim analyses utilized O’Brien-Fleming efficacy and futility monitoring boundaries. The Cochran-Mantel-Haenszel test compared the proportion of pts with high bleeding scores (WHO ≥2 or MBS ≥3) between the two arms. A t-test compared the number of rescue therapies and the absolute change in KIT score between the two arms.

Results: The epag arm had a statistically significant higher proportion of responders as compared to the SOC arm (p=0.0023; z-score=3.04) in the second planned interim analysis, crossing the monitoring boundary for efficacy for the primary endpoint. The primary endpoint of platelet response was achieved by 51/78 (65%) pts in the epag arm, compared with 13/40 (33%) pts in the SOC arm (p=0.0007). Trial accrual was closed early for efficacy per DSMB recommendation.

Between May 2019 – January 2024, 122 pts were randomized across 23 institutions; 4 pts were subsequently deemed ineligible, and 118 were included in the intent-to-treat analysis (n=78 epag, n=40 SOC). Of the 118, 46 were aged 1-<6 years, 42 aged 6-<12 years, and 30 aged 12-<18 years. Forty-six pts received upfront treatment on the study, and 72 pts had treatment failure prior to enrollment. Median platelet count at enrollment was 4 x109/L (range 1 – 23) in the epag arm and 8 x109/L (1 – 28) in the SOC arm. Median WHO bleeding score at enrollment was 2 (range 0 – 3) and MBS was 3 (range 0 – 3) in the epag arm and 1 (0 – 3) and 2 (0 – 3), respectively, in the SOC arm. In the SOC arm, treatments prescribed were prednisone (n=29) and IVIg (n=11).

The proportion of pts with a high bleeding score in the epag vs SOC arm was similar at weeks 1-4 and week 12. The proportion of pts who received rescue therapy was lower in the epag arm [15/78 (19%)] than the SOC arm [18/39 (46%)] (p=0.002). The mean absolute change from baseline in parent proxy-reported KIT overall scores in the epag arm vs SOC arm was 8.7 vs 10.1 at 1 week (p=0.45), 13.4 vs 10.7 at 4 weeks (p=0.24), and 15.6 vs 11.2 at 12 weeks (p=0.14), consistent with a clinically meaningful improvement in QoL at all time points in both arms.

There were 20 AEs grade 3 or higher (including 6 SAEs) in the epag arm, and 6 (3 SAEs) in the SOC arm during the first 12 weeks. The most common AEs were headache (3 epag, 3 SOC) and epistaxis (1 epag, 2 SOC). Drug-related SAEs occurred in 6 pts (epag – 2 elevated LFTs, 2 headache (HA); SOC – 1 allergic reaction, 1 HA). There were no thromboembolic events. There was 1 intracranial hemorrhage in the epag arm.

Enrolled pts are completing 12 months of follow up on the study per protocol.

Conclusion: In pediatric pts with newly diagnosed ITP requiring pharmacologic treatment, epag leads to a significantly higher rate of a durable platelet response in the absence of rescue treatments as compared with standard first-line therapies.

Disclosures: Shimano: Sanofi: Research Funding; Sobi: Research Funding; Daiichi Sankyo: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Grimes: Novartis: Research Funding. Rose: F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.; Genentech Advisory Board/Consulting: Consultancy. Kaicker: CSL Behring: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Shah: Sobi: Honoraria. Lebensburger: Pfizer: Consultancy; Agios: Consultancy; Novartis: Consultancy. Lambert: FWGBD, PDSA, NIH, Sysmex, Novartis, Principia, Argenx, Dova, Octapharma and Sanofi: Research Funding; Octapharma, Dova, Principia, Rigel, Argenx, PDSA, 22qSociety and CdLS Foundation: Membership on an entity's Board of Directors or advisory committees; Novartis Dova, Principia, Argenx, Rigel, Sobi, Sanofi and Janssen: Consultancy. Fritch Lilla: Chiesi: Speakers Bureau; Sobi: Honoraria; Octapharma: Consultancy; Agios: Honoraria. Jesudas: Merck: Consultancy, Honoraria. Thompson: CRISPR/Vertex: Consultancy, Research Funding; Novartis: Research Funding; Editas: Consultancy, Research Funding; Beam Therapeutics: Consultancy, Research Funding; Global Blood Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; bluebird bio: Consultancy, Research Funding. Rifkin-Zenenberg: Vertex: Honoraria, Membership on an entity's Board of Directors or advisory committees. Crary: Novartis: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; Medexus: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; ASC Therapeutics: Consultancy; CSL Behring: Membership on an entity's Board of Directors or advisory committees. Rothman: Agios: Consultancy, Research Funding; Blue Bird Bio: Research Funding; Dova: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sobi: Research Funding. London: Jubilant Draximage Inc: Consultancy; Y-mAbs Therapeutics, Inc: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy. Bennett: Spark Therapeutics: Current Employment. Despotovic: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Klaassen: Octapharma AG: Consultancy; Novo Nordisk: Consultancy; Hoffman La Roche: Consultancy; Bayer Canada: Consultancy; Amgen Inc: Consultancy; Agios Pharmaceuticals: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. Neufeld: Novartis: Research Funding; Merck: Consultancy; Agios: Consultancy; Sobi: Consultancy; LFB: Consultancy; Saliogen Pharma: Consultancy, Current equity holder in private company; Takeda: Consultancy; Pfizer: Consultancy; Genentech: Consultancy. Neunert: UpToDate: Patents & Royalties; Argenx: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Grace: Agios, Sanofi, Sobi: Consultancy; Agios, Sobi, Novartis: Research Funding.

OffLabel Disclosure: Eltrombopag is a thrombopoietin receptor agonist. It is FDA approved for children with chronic ITP. This trial investigates its use in children with newly diagnosed ITP.

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