Optimal therapy for pediatric B-ALL in first relapse: Comparative effectiveness of blinatumomab to hematopoietic cell transplantation versus CD19 CAR T cell therapy
Abstract
Abstract INTRODUCTION Outcomes for 1st relapse of pediatric B-lymphoblastic leukemia (B-ALL), especially high/intermediate-risk (HR/IR) relapse, remain unacceptably poor. Limited enrollment of this population on cooperative group clinical trials has impeded our ability to study potentially effective regimens. In the current era, patients can access innovative immunotherapies commercially. However, there is no mechanism to capture outcomes for these off-study patients and no comparative effectiveness data to guide treatment selection. METHODS We conducted a multicenter, retrospective study of patients <30 years who initiated 1st relapse therapy at a participating center from 2018-2022 (ReCALL-1 Study). Objectives were to define real-world survival outcomes, compare response rates of reinduction strategies, describe the post-reinduction treatment landscape, and, for patients with HR/IR relapse, assess the comparative effectiveness (CE) of blinatumomab to hematopoietic cell transplant (blina/HCT) v CD19 CAR T cells (CART). For the CE analysis, we emulated an open-label, randomized study of blina/HCT v CART who achieved an M1/M2 marrow at the end of an intensive reinduction (EoRI). Patients were classified by their intended treatment at EoRI. Cox regression models were used to adjust for unbalanced patient and disease features by arms. The primary outcome was overall survival (OS) from EoRI. RESULTS The full cohort included 479 patients from 33 centers (31 US, 2 international). Median time to relapse was 31 months (m); 77% had bone marrow (BM) involvement and 31% central nervous sytem involvement. With a median follow-up of 49m from relapse, 4 year (y) OS, event-free survival (EFS), and non-relapse mortality (NRM) were 64%, 43%, and 13%, respectively. Among patients with very early BM (<18m, n=79), early BM (18-35m, n=76), late BM (≥36m, n=162), and isolated CNS (n=85) relapses, 4y OS/EFS were 29%/20%, 57%/35%, 78%/49%, and 84%/61%, respectively. Only 19% received reinduction therapy on a clinical trial. Among patients with BM disease, R3 reinduction (n=179) and VXLD (n=61) had identical MRD-negative (<0.01%) CR rates of 38% (p=1.00) and equivalent treatment failure (TF; M3 or extramedullary disease) rates: R3, 8% v VXLD 7%, p=0.79. Blina (n=33) and inotuzumab-based (n=21) reinductions achieved MRD-negative CR rates of 39% and 52%, respectively, but higher TF rates of 39% and 24%. Reinduction mortality was 2%: R3, n=5; VXLD, n=3; 3-drug reinduction, n=1. Overall, as part of 1st relapse therapy, 36% received CART (78% commercial product), 44% HCT, 40% blina, and 11% inotuzumab. The emulated trial included 159 patients, 95 on blina/HCT and 64 on CART. Study arms were well matched by demographics, cytogenetics, and relapse sites, but CART patients were more likely to have relapsed <18m from diagnosis (34% v 24%) and have EoRI M2 marrows (31% v 11%), and less likely to have private insurance (36% v 51%). Unadjusted OS was comparable between arms (log rank p=0.18): CART, 60% at 4y; blina/HCT, 71%, as was NRM (10% v 13% at 4y). EFS was lower for CART (p=0.049): 4y EFS 35% v 49% for blina/HCT. After adjustment for unbalanced covariates, the hazard of death was equivalent for CART as compared to blina/HCT (aHR 1.1, 95% CI 0.6-2.1, p=0.67) and EFS became more comparable (aHR 1.3, 95% CI 0.8-2.1, p=0.22). 91% of blina/HCT and 97% of CART received their intended cell therapy; time from EoRI to cell therapy was shorter for CART (67 v 86 days, p<.001). In the CART arm, 34% underwent consolidative HCT; 1/3 were preplanned and 2/3 due to loss of B cell aplasia or NGS-MRD positivity. Of those with a 2nd relapse, CART patients were more likely to be CD19 negative (47% v 10%, p=0.003). CONCLUSION In this multicenter, real-world cohort of children treated for 1st relapse in the immunotherapy era, suboptimal outcomes for early BM relapse persisted, with particularly dismal 4y OS of 29% for relapses <18m after diagnosis. In contrast, survival for late BM and isolated CNS relapses compared favorably to historic data. Only 1 in 5 patients initiated relapse therapy on a clinical trial and although 1st relapse is not an approved indication for commercial CART in pediatrics, 36% received CART. In an emulated trial of post-reinduction blina/HCT v CART, adjusted EFS and OS were comparable, suggesting that CART may be a viable alternative to HCT for select patients. Post hoc analyses will identify whether specific subgroups may benefit more from one strategy.
Article Details
Authors (66)
Regina Myers
1Children's Hospital of Philadelphia, Division of Oncology, Philadelphia, United States
Yimei Li
Hongyan Liu
CAS Key Laboratory of Green Process and Engineering, State Key Laboratory of Multiphase Complex Systems, Beijing Key Laboratory of Ionic Liquids Clean Process, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
Alex Hoover
Laura Shinehouse
1Children's Hospital of Philadelphia, Division of Oncology, Philadelphia, United States
Ashley Hinson
3Atrium Health Levine Children's Hospital, Department of Pediatric Hematology and Oncology, Charlotte, United States
Mira Kohorst
4Mayo Clinic Children's, Division of Pediatric Hematology-Oncology, Rochester, United States
Anna Elias
4Mayo Clinic Children's, Division of Pediatric Hematology-Oncology, Rochester, United States
Ella Keenan
1Children's Hospital of Philadelphia, Division of Oncology, Philadelphia, United States
Hannah Acres
5University of Texas Southwestern Medical Center, Department of Pediatrics, Dallas, United States
Ibrahim Ahmed
Abdulla Al-Mulla
7Children's Hospital of Richmond at VCU, Division of Oncology, Richmond, United States
Laura Arthur
8Lurie Children's Hospital, Division of Hematology, Oncology, Neuro-Oncology, & Stem-Cell Transplant, Chicago, United States
Jill Beck
9University of Nebraska Medical Center, Division of Pediatric Hematology/Oncology, Omaha, United States
Abigale Berry
1Children's Hospital of Philadelphia, Division of Oncology, Philadelphia, United States
Deepika Bhatla
10Cardinal Glennon Children's Hospital, Division of Oncology, Saint Louis, United States
Eliza Briscoe
11University of Utah/Primary Children's Hospital, Department of Pediatrics, Salt Lake City, United States
Grace Chang
Roland Chu
13Children's Hospital of Michigan, Division of Pediatric Hematology/Oncology, Detroit, United States
Laurie Davis
14Baylor College of Medicine, Division of Blood and Marrow Transplant, San Antonio, United States
J. Gregory Dolan
22Division of Hematology and Oncology, Intermountain Primary Children's Hospital, Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, United States
Lyannette Elo
14Baylor College of Medicine, Division of Blood and Marrow Transplant, San Antonio, United States
Elizabeth Eom
15Children's Hospital Los Angeles, Division of Hematology-Oncology, Los Angeles, United States
Alejandra Escobar Vasco
16Medical College of Wisconsin, Division of Pediatric Hematology/Oncology/Blood and Marrow Transplant, Department of Pediatrics, Milwaukee, United States
Vanessa Fabrizio
6Division of Pediatric Hematology-Oncology-BMT, University of Colorado, Aurora, United States
Kelly Faulk
17Children's Hospital of Colorado, Center for Cancer and Blood Disorders, Department of Pediatrics, Aurora, United States
Victor Galan-Gomez
18Hospital Universitario La Paz, Pediatric Hemato-Oncology Unit, Madrid, Spain
Erin Goode
2Peter MacCallum Cancer Centre, Department of Pathology, Melbourne, Australia
Stephan Grupp
1Children's Hospital of Philadelphia, Division of Oncology, Philadelphia, United States
Anurekha Hall
12Seattle Children's Hospital, Seattle, WA, Division of Oncology, Seattle, United States
Darcy Hamill
Smitha Vasanna
20Arkansas Children's Hospital, Pediatric Oncology, Bone Marrow Transplant and Cellular Therapies, Little Rock, United States
Hannah Kinoshita
21Children's National Hospital, Center for Cancer and Blood Disorders, Washington, United States
Elizabeth Krieger
3Virginia Commonwealth University, Department of Pediatrics, Richmond, United States
Cathy Lee-Miller
22University of Wisconsin School of Medicine and Public Health, Department of Pediatrics, Division of Hematology, Oncology, Transplant & Cell Therapy, Madison, United States
Katherine Lind
17Children's Hospital of Colorado, Center for Cancer and Blood Disorders, Department of Pediatrics, Aurora, United States
Jordan Milner
11Department of Pediatrics, Division of Hematology/Oncology, University of Florida, UF Health Shands Children's Hospital, Gainesville, United States
Giselle Moore-Higgs
23University of Florida, Division of Oncology, Gainesville, United States
Amy Moskop
16Medical College of Wisconsin, Division of Pediatric Hematology/Oncology/Blood and Marrow Transplant, Department of Pediatrics, Milwaukee, United States
Lindsey Murphy
1City of Hope, Pediatrics, Duarte, United States
Megan Murphy
25Johns Hopkins Hospital, Division of Pediatric Oncology, Department of Oncology, Baltimore, United States
Gabriella Nguyen
5University of Texas Southwestern Medical Center, Department of Pediatrics, Dallas, United States
Maria Ortega
19Nemours Children's Health, Lisa Dean Moseley Foundation for Cancer and Blood Disorders, Wilmington, United States
Hiren Patel
26Cohen Children's Medical Center, Division of Pediatric Hematology/Oncology and Cellular Therapy, New Hyde Park, United States
Antonio Perez
18Hospital Universitario La Paz, Pediatric Hemato-Oncology Unit, Madrid, Spain
Thomas Pfeiffer
Alexandra Prosser-Dombrowski
6Children's Mercy Kansas City, Division of Hematology/Oncology/Bone Marrow Transplant, Kansas City, United States
Mahvish Rahim
28Children's Hospital at Montefiore, Division of Pediatric Hematology, Oncology, and Stem Cell Transplant, Bronx, United States
April Rahrig
29Riley Hospital for Children, Division of Pediatric Hematology, Oncology and Stem Cell Transplant, Indianapolis, United States
Shanti Ramachandran
30Perth Children's Hospital, Department of Clinical Haematology, Oncology and Bone Marrow Transplantation, Nedlands, Australia
Miza Salim Hammoud
Amanda Saraf
1Riley Children's Health, Indianapolis, United States
Jamie Shoag
31Cleveland Clinic Children's, Division of Pediatric Hematology and Oncology, Cleveland, United States
Heather Symons
25Johns Hopkins Hospital, Division of Pediatric Oncology, Department of Oncology, Baltimore, United States
Nicholas Tastet
3Atrium Health Levine Children's Hospital, Department of Pediatric Hematology and Oncology, Charlotte, United States
Stephanie Thomas
20Arkansas Children's Hospital, Pediatric Oncology, Bone Marrow Transplant and Cellular Therapies, Little Rock, United States
Molly Thornock
2City of Hope, Population Sciences, Duarte, United States
Keri Toner
21Children's National Hospital, Center for Cancer and Blood Disorders, Washington, United States
Allison Weisnicht
22University of Wisconsin School of Medicine and Public Health, Department of Pediatrics, Division of Hematology, Oncology, Transplant & Cell Therapy, Madison, United States
Sara Zarnegar-Lumley
8Lurie Children's Hospital, Division of Hematology, Oncology, Neuro-Oncology, & Stem-Cell Transplant, Chicago, United States
Nirali Shah
32National Cancer Institute, Pediatric Oncology Branch, Bethesda, United States
Shannon Maude
1Children's Hospital of Philadelphia, Division of Oncology, Philadelphia, United States
Jeremy Rubinstein
33Cincinnati Children's Hospital Medical Center, Division of Oncology, Cincinnati, United States
Troy Quigg
2Section of Pediatric Bone Marrow Transplantation and Cellular Therapy, Helen DeVos Children's Hospital, Grand Rapids, United States
Deepa Bhojwani
Caitlin Elgarten
University of Pennsylvania, Philadelphia