An investigation of toxicities and survival in Hispanic children and adolescents with ALL: Results from the Dana-Farber Cancer Institute ALL Consortium protocol 05-001
Corresponding Author
Justine M. Kahn
Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, New York, New York
Correspondence
Justine M. Kahn, Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, 161 Fort Washington Avenue, IP7, New York, NY 10032.
Email: [email protected]
Search for more papers by this authorPeter D. Cole
Division of Pediatric Hematology/Oncology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York
Search for more papers by this authorTraci M. Blonquist
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
Search for more papers by this authorKristen Stevenson
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
Search for more papers by this authorZhezhen Jin
Department of Biostatistics, Columbia University Medical Center, New York, New York
Search for more papers by this authorSergio Barrera
Department of Economics, University of Minnesota, Minneapolis, Minnesota
Search for more papers by this authorRandy Davila
Department of Psychology, University of California, Davis, California
Search for more papers by this authorEmily Roberts
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan
Search for more papers by this authorDonna S. Neuberg
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
Search for more papers by this authorUma H. Athale
Division of Pediatric Hematology/Oncology, McMaster University, Hamilton, Ontario, Canada
Search for more papers by this authorLuis A. Clavell
Division of Pediatric Oncology, San Jorge Children's Hospital, San Juan, Puerto Rico
Search for more papers by this authorCaroline Laverdiere
Division of Hematology and Oncology, Hospital Sainte-Justine, University of Montreal, Montreal, Canada
Search for more papers by this authorJean-Marie Leclerc
Division of Hematology and Oncology, Hospital Sainte-Justine, University of Montreal, Montreal, Canada
Search for more papers by this authorBruno Michon
Division of Hematology-Oncology, Centre Hospitalier de l'Université Laval, Quebec City, Canada
Search for more papers by this authorMarshall A. Schorin
Inova Fairfax Hospital for Children, Falls Church, Virginia
Search for more papers by this authorJennifer J.G. Welch
Division of Pediatric Hematology-Oncology, Hasbro Children's Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
Search for more papers by this authorStephen E. Sallan
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts
Search for more papers by this authorLewis B. Silverman
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts
Search for more papers by this authorKara M. Kelly
Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, New York, New York
Roswell Park Cancer Institute and Women and Children's Hospital, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York
Search for more papers by this authorCorresponding Author
Justine M. Kahn
Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, New York, New York
Correspondence
Justine M. Kahn, Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, 161 Fort Washington Avenue, IP7, New York, NY 10032.
Email: [email protected]
Search for more papers by this authorPeter D. Cole
Division of Pediatric Hematology/Oncology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York
Search for more papers by this authorTraci M. Blonquist
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
Search for more papers by this authorKristen Stevenson
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
Search for more papers by this authorZhezhen Jin
Department of Biostatistics, Columbia University Medical Center, New York, New York
Search for more papers by this authorSergio Barrera
Department of Economics, University of Minnesota, Minneapolis, Minnesota
Search for more papers by this authorRandy Davila
Department of Psychology, University of California, Davis, California
Search for more papers by this authorEmily Roberts
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan
Search for more papers by this authorDonna S. Neuberg
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
Search for more papers by this authorUma H. Athale
Division of Pediatric Hematology/Oncology, McMaster University, Hamilton, Ontario, Canada
Search for more papers by this authorLuis A. Clavell
Division of Pediatric Oncology, San Jorge Children's Hospital, San Juan, Puerto Rico
Search for more papers by this authorCaroline Laverdiere
Division of Hematology and Oncology, Hospital Sainte-Justine, University of Montreal, Montreal, Canada
Search for more papers by this authorJean-Marie Leclerc
Division of Hematology and Oncology, Hospital Sainte-Justine, University of Montreal, Montreal, Canada
Search for more papers by this authorBruno Michon
Division of Hematology-Oncology, Centre Hospitalier de l'Université Laval, Quebec City, Canada
Search for more papers by this authorMarshall A. Schorin
Inova Fairfax Hospital for Children, Falls Church, Virginia
Search for more papers by this authorJennifer J.G. Welch
Division of Pediatric Hematology-Oncology, Hasbro Children's Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
Search for more papers by this authorStephen E. Sallan
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts
Search for more papers by this authorLewis B. Silverman
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts
Search for more papers by this authorKara M. Kelly
Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, New York, New York
Roswell Park Cancer Institute and Women and Children's Hospital, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York
Search for more papers by this authorFunding information: Grant sponsor: National Institutes of Health (R25 CA094061); Grant sponsor: St. Baldrick's Foundation (Supportive Care Research Award).
Presented in abstract form at the 56th American Society of Hematology Annual Meeting and Exposition, December 5–8, 2015, Orlando, FL, USA.
Abstract
Purpose
This study compared the relative incidence of treatment-related toxicities and the event-free and overall survival between Hispanic and non-Hispanic children undergoing therapy for acute lymphoblastic leukemia (ALL) on Dana-Farber Cancer Institute ALL Consortium protocol 05-001.
Patients and methods
Secondary analysis of prospectively collected data from a phase III multicenter study in children and adolescents of 1–18 years with previously untreated ALL.
Results
Between 2005 and 2011, 794 eligible patients enrolled on DFCI 05-001, 730 of whom were included in this analysis (19% [N = 150] Hispanic, 73% [N = 580] non-Hispanic). Hispanic patients were more likely to be ≥10 years of age (32% vs. 24%, P = 0.045) at diagnosis. Toxicity analyses revealed that Hispanic patients had significantly lower cumulative incidence of bone fracture (P < 0.001) and osteonecrosis (ON; P = 0.047). In multivariable risk regression, the risk of ON was significantly lower in Hispanic patients ≥10 years (HR 0.23; P = 0.006). Hispanic patients had significantly lower 5-year event-free survival (EFS) (79.4%; 95% CI: 71.6–85.2) and overall survival (OS) (89.2%; 95% CI: 82.7–93.4) than non-Hispanic patients (EFS: 87.5%; 95% CI: 84.5–90.0, P = 0.004; OS: 92.7%; 95% CI: 90.2–94.6, P = 0.006). Exploratory analyses revealed differences between Hispanic and non-Hispanic patients in the frequency of common variants in genes related to toxicity or ALL outcome.
Conclusion
Hispanic children treated for ALL on DFCI 05-001 had fewer bone-related toxicities and inferior survival than non-Hispanic patients. While disease biology is one explanatory variable for outcome disparities, these findings suggest that biologic and non-biologic mechanisms affecting drug delivery and exposure in this population may be important contributing factors as well.
CONFLICT OF INTEREST
L.B.S. has served on advisory boards for Sigma-Tau Pharmaceuticals and JAZZ Pharmaceuticals. All other authors declare no conflict of interest.
Supporting Information
| Filename | Description |
|---|---|
| pbc26871-sup-0002-Table-S1.docx44.8 KB | Supplemental Table S1: Events in Hispanic and non-Hispanic patients. Both Hispanic and non-Hispanic patients had nearly identical complete remission (CR) rates (94-95%), however, a higher percentage of Hispanic vs. non-Hispanic (13% vs. 9%) patients experienced disease relapse. |
| pbc26871-sup-0003-Table-S2.docx47.8 KB | Supplemental Table S2: Distribution of sites of relapse by ethnicity. There was no significant difference in sites of relapse between Hispanic and non-Hispanic patients. |
| pbc26871-sup-0004-Table-S3.docx109.5 KB | Supplemental Table S3: Target polymorphisms by ethnicity. Hispanic and non-Hispanic patients differed significantly in the proportion with the target genotype of four polymorphic genes: MTHFR A1298C (rs1801131; padjusted = 0.001), SLCO2A1 (padjusted = 0.003), IL1B (padjusted = 0.003), and TCN2 (padjusted = 0.002). |
| pbc26871-sup-0005-Table-S4.docx91.2 KB | Supplemental Table S4: Analyses of polymorphisms versus disease-free survival (DFS) and event-free survival (EFS) in Hispanic and non-Hispanic patients with nominal p-values, overall and by ethnicity. In the Hispanic cohort, the TCN2 polymorphism was univariately associated with EFS within the Hispanic patient cohort. In multivariable modeling, TCN2 was marginally associated with EFS (HR = 3.15, p = 0.05). |
| pbc26871-sup-0001-Figure-S1copy.png622 KB | Supplemental Figure S1: Median (IQR) serum asparaginase activity levels in Hispanic and Non-Hispanic patients: during remission induction, when all patients received a single dose of pegasapargase, median serum asparaginase activity (SAA) was measured 4 (D4), 11 (D11), 18 (D18), and 25 (D25) days after the dose. At least one induction SAA level was available in 318 patients. At D4, n = 289, D11, n = 318, D18 n = 271, and D25 n = 274. We did not observed differences between Hispanic and non-Hispanic patients in median SAA levels 4, 11, 18, and 25 days after a dose. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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