Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study

Susan R Rheingold^#¹, Deepa Bhojwani^#², Lingyun Ji³, Xinxin Xu⁴, Meenakshi Devidas⁵, John A Kairalla⁶, Mary Shago⁷, Nyla A Heerema⁸, Andrew J Carroll⁹, Heather Breidenbach¹⁰, Michael Borowitz¹¹, Brent L Wood¹², Anne L Angiolillo¹³, Barbara L Asselin¹⁴, W Paul Bowman¹⁵, Patrick Brown¹⁶, ZoAnn E Dreyer¹⁷, Kimberly P Dunsmore¹⁸, Joanne M Hilden¹⁹, Eric Larsen²⁰, Kelly Maloney¹⁹, Yousif Matloub²¹, Leonard A Mattano²², Stuart S Winter²³, Lia Gore¹⁹, Naomi J Winick²⁴, William L Carroll²⁵, Stephen P Hunger²⁶, Elizabeth A Raetz²⁵, Mignon L Loh²⁷

Affiliations

¹ Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. rheingold@chop.edu.
² Division of Pediatric Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center and Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁴ Children's Oncology Group, Monrovia, CA, USA.
⁵ Department of Global Pediatric Medicine, St Jude Children's Research Hospital, Memphis, TN, USA.
⁶ Department of Biostatistics, University of Florida, Gainesville, FL, USA.
⁷ Department of Laboratory Medicine and Pathobiology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
⁸ Department of Pathology, The Ohio State University, Columbus, OH, USA.
⁹ Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁰ The Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Department of Pathology and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
¹² Department of Pathology and Laboratory Medicine, Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹³ Servier Pharmaceuticals, Boston, MA, USA.
¹⁴ Department of Pediatrics, Golisano Children's Hospital, Wilmot Cancer Center at University of Rochester Medical Center, Rochester, New York, NY, USA.
¹⁵ Cook Children's Medical Center, Fort Worth, TX, USA.
¹⁶ Bristol Myers Squibb, Princeton, NJ, USA.
¹⁷ Department of Pediatrics, Section of Hematology/Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
¹⁸ Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, USA.
¹⁹ Department of Pediatrics, University of Colorado School of Medicine and Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA.
²⁰ Department of Pediatrics, Maine Medical Center, Portland, ME, USA.
²¹ Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA.
²² HARP Pharma Consulting, Mystic, CT, USA.
²³ Cancer and Blood Disorders Program, Children's Minnesota, Minneapolis, MN, USA.
²⁴ Department of Pediatrics, University of Texas Southwestern Medical Center, Childrens Health, Dallas, TX, USA.
²⁵ Perlmutter Cancer Center, Department of Pediatrics, NYU Grossman School of Medicine, New York, NY, USA.
²⁶ Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁷ Department of Pediatrics, Seattle Children's Hospital, Seattle, WA, USA.

^# Contributed equally.

PMID: 39261601
PMCID: PMC11518984
DOI: 10.1038/s41375-024-02395-4

Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study

Susan R Rheingold et al. Leukemia. 2024 Nov.

. 2024 Nov;38(11):2382-2394.

doi: 10.1038/s41375-024-02395-4. Epub 2024 Sep 11.

Authors

Affiliations

¹ Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. rheingold@chop.edu.
² Division of Pediatric Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center and Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁴ Children's Oncology Group, Monrovia, CA, USA.
⁵ Department of Global Pediatric Medicine, St Jude Children's Research Hospital, Memphis, TN, USA.
⁶ Department of Biostatistics, University of Florida, Gainesville, FL, USA.
⁷ Department of Laboratory Medicine and Pathobiology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
⁸ Department of Pathology, The Ohio State University, Columbus, OH, USA.
⁹ Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁰ The Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Department of Pathology and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
¹² Department of Pathology and Laboratory Medicine, Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹³ Servier Pharmaceuticals, Boston, MA, USA.
¹⁴ Department of Pediatrics, Golisano Children's Hospital, Wilmot Cancer Center at University of Rochester Medical Center, Rochester, New York, NY, USA.
¹⁵ Cook Children's Medical Center, Fort Worth, TX, USA.
¹⁶ Bristol Myers Squibb, Princeton, NJ, USA.
¹⁷ Department of Pediatrics, Section of Hematology/Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
¹⁸ Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, USA.
¹⁹ Department of Pediatrics, University of Colorado School of Medicine and Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA.
²⁰ Department of Pediatrics, Maine Medical Center, Portland, ME, USA.
²¹ Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA.
²² HARP Pharma Consulting, Mystic, CT, USA.
²³ Cancer and Blood Disorders Program, Children's Minnesota, Minneapolis, MN, USA.
²⁴ Department of Pediatrics, University of Texas Southwestern Medical Center, Childrens Health, Dallas, TX, USA.
²⁵ Perlmutter Cancer Center, Department of Pediatrics, NYU Grossman School of Medicine, New York, NY, USA.
²⁶ Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁷ Department of Pediatrics, Seattle Children's Hospital, Seattle, WA, USA.

^# Contributed equally.

PMID: 39261601
PMCID: PMC11518984
DOI: 10.1038/s41375-024-02395-4

Abstract

Limited prognostic factors have been associated with overall survival (OS) post-relapse in childhood Acute Lymphoblastic Leukemia (ALL). Patients enrolled on 12 Children's Oncology Group frontline ALL trials (1996-2014) were analyzed to assess for additional prognostic factors associated with OS post-relapse. Among 16,115 patients, 2053 (12.7%) relapsed. Relapse rates were similar for B-ALL (12.5%) and T-ALL (11.2%) while higher for infants (34.2%). Approximately 50% of B-ALL relapses occurred late (≥36 months) and 72.5% involved the marrow. Conversely, 64.8% of T-ALL relapses occurred early (<18 months) and 47.1% involved the central nervous system. The 5-year OS post-relapse for the entire cohort was 48.9 ± 1.2%; B-ALL:52.5 ± 1.3%, T-ALL:35.5 ± 3.3%, and infant ALL:21.5 ± 3.9%. OS varied by early, intermediate and late time-to-relapse; 25.8 ± 2.4%, 49.5 ± 2.2%, and 66.4 ± 1.8% respectively for B-ALL and 29.8 ± 3.9%, 33.3 ± 7.6%, 58 ± 9.8% for T-ALL. Patients with ETV6::RUNX1 or Trisomy 4 + 10 had median time-to-relapse of 43 months and higher OS post-relapse 74.4 ± 3.1% and 70.2 ± 3.6%, respectively. Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short median time-to-relapse (12.5-18 months) and poor OS post-relapse (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%). Site-of-relapse varied by cytogenetic subtype. This large dataset provided the opportunity to identify risk factors for OS post-relapse to inform trial design and highlight populations with dismal outcomes post-relapse.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Time and site of relapse.**
Patterns of first relapse differed between (A) B-ALL, (B) T-ALL, (C) Infant ALL. iBM isolated bone marrow, BM bone marrow, CNS central nervous system, iCNS isolated central nervous system.

**Fig. 2. Overall survival post first relapse.**
Kaplan–Meier estimates of overall survival rates post relapse based on (A) mmunophenotype, (B) B-ALL time to relapse, (C) B-ALL site of relapse, (D) B-ALL cytogenetic subtype, (E) T-ALL time to relapse, (F) T-ALL site of relapse, (G) Infant ALL cytogenetic subtype, (H) Infant ALL time to relapse, (I) Infant ALL site of relapse.

See this image and copyright information in PMC

References

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Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study

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Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study

Authors

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Abstract

Conflict of interest statement

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