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Research Articles

Causes of Inferior Outcome in Adolescents and Young Adults with Acute Lymphoblastic Leukemia: Across Oncology Services and Regardless of Clinical Trial Enrollment

Julie A. Wolfson, Joshua S. Richman, Can-Lan Sun, Wendy Landier, Karen Leung, Eileen P. Smith, Margaret O’Donnell and Smita Bhatia
Julie A. Wolfson
1Institute for Cancer Outcomes and Survivorship, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
2Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.
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  • ORCID record for Julie A. Wolfson
  • For correspondence: jwolfson@peds.uab.edu
Joshua S. Richman
3Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama.
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Can-Lan Sun
4Department of Population Sciences, City of Hope, Duarte, California.
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Wendy Landier
1Institute for Cancer Outcomes and Survivorship, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
2Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.
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Karen Leung
4Department of Population Sciences, City of Hope, Duarte, California.
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Eileen P. Smith
5Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
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Margaret O’Donnell
5Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
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Smita Bhatia
1Institute for Cancer Outcomes and Survivorship, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
2Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.
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DOI: 10.1158/1055-9965.EPI-18-0430 Published October 2018
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    Figure 1.

    AYA and children with ALL: 5-year relapse-free survival by age group.

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    Figure 2.

    Hazard of relapse in AYA and children with ALL. Smoothed plot of risk of relapse per month, stratified by age (AYA vs. child) for the following groups: A, Overall hazard of relapse from first CR1 to 10 years. B, Hazard of relapse during treatment from CR1. C, Hazard of relapse after completion of treatment (from date of last treatment). Shaded areas indicate confidence regions.

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  • Table 1.

    Characteristics of children and AYA with ALL

    TotalChild: 1–14 yAYA: 15–39 y
    (n = 184)(n = 91)(n = 93)P
    Sociodemographics
     Age
      Median (interquartile range)15 y (4.75–34 y)4 y (3–10 y)23 y (19–30 y)
     Gender
      Male119 (64.7%)56 (61.5%)63 (67.7%)0.4
      Female65 (35.3%)35 (38.5%)30 (32.3%)
     Race/ethnicity
      Non-Hispanic white63 (34.2%)30 (33.0%)33 (35.5%)0.1
      African-American1 (0.5%)0 (0%)1 (1.1%)
      Hispanic99 (53.8%)46 (50.6%)53 (57.0%)
      Asian-Pacific Islander21 (11.4%)15 (16.5%)6 (6.5%)
     Insurance
      Private85 (46.2%)48 (52.8%)37 (39.8%)0.2
      Public66 (35.9%)30 (33.0%)36(38.7%)
      No insurance/unknown33 (17.9%)13 (14.3%)20 (21.5%)
     SES
      Low32 (17.4%)10 (11.0%)22 (23.7%)0.2
      Mid-Low36 (19.6%)18 (19.8%)18 (19.4%)
      Mid39 (21.2%)23 (25.3%)16 (17.2%)
      Mid-High39 (21.2%)20 (22.0%)19 (20.4%)
      High38 (20.7%)20 (22.0%)18 (19.4%)
     Insurance + SES combined
      Private insurance + high SES47 (25.5%)26 (28.6%)21 (22.6%)0.3
      Public/none + mid/low SES69 (37.5%)29 (31.9%)40 (43.0%)
      Mixed profilea68 (37.0%)34 (31.9%)32 (34.4%)
    Treatment variables
     Therapy
      Pediatric102 (55.4%)84 (92.3%)18 (19.4%)<0.0001
      Adult65 (35.3%)0 (0%)65 (69.9%)
      Mixed7 (3.8%)0 (0%)7 (7.5%)
      International10 (5.4%)7 (7.7%)3 (3.2%)
     Oncology service
      Pediatric101 (54.9%)84 (92.3%)17 (18.3%)<0.0001
      Adult71 (38.6%)0 (0%)71 (76.3%)
      Mixed2 (1.1%)0 (0%)2 (2.2%)
      International10 (5.4%)7 (7.7%)3 (3.2%)
     Oncology service + therapy
      Pediatric oncology/pediatric therapy101 (54.9%)84 (92.3%)17 (18.3%)<0.0001
      Adult oncology/adult therapy65 (35.3%)0 (0%)65 (69.9%)
      Mixed oncology/mixed therapy18 (9.8%)7 (7.7%)11 (11.8%)
     Duration of maintenance mean (SD) in months
      All patients19 (11.2)23.5 (8.5)14.9 (12)<0.01
      Patients who completed therapy25.4 (6.8)25.3 (6.5)25.4 (7.3)0.9
     Duration of consolidation mean (SD) in months
      All patients7.2 (3.6)8.0 (3.6)6.5 (3.5)<0.01
      Patients who completed therapy8.0 (3.5)8.2 (3.6)7.7 (3.4)0.5
     Clinical trial enrollment
      Enrolled on clinical trial60 (32.6%)39 (42.9%)21 (22.6%)0.003
      Not enrolled on clinical trial124 (67.4%)52 (57.1%)72 (77.4%)
    Clinical prognosticators
     White blood cell count at diagnosis
      WBC <50K129 (70.1%)67 (73.6%)62 (66.7%)0.3
      WBC >50K55 (29.9%)24 (26.4%)31 (33.3%)
     Response to therapy at the end of inductionb
      M1 marrow at end of Induction139 (75.5%)78 (85.7%)61 (65.6%)<0.01
      M2-M3 marrow at end of Induction18 (9.8%)4 (4.4%)14 (15.1%)
      Other27 (14.7%)9 (9.9%)18 (19.4%)
     Immunophenotype
      Precursor B-cell149 (81%)79 (86.8%)70 (75.3%)0.04
      T-cell35 (19%)12 (13.2%)23 (24.7%)
     High-risk cytogenetic profilec
      High-risk cytogenetic profile18 (9.8%)5 (5.5%)13 (14.0%)0.05
      No presence of high-risk features166 (90.2%)86 (94.5%)80 (86%)
     CNS disease
      Positive6 (3.3%)2 (2.2%)4 (4.3%)0.3
      Negative168 (91.3%)86 (94.5%)82 (88.2%)
      Unknown10 (5.4%)3 (3.3%)7 (7.5%)
    • ↵aMixed profile in this situation reflects a combination of either public or no insurance + high SES, or private insurance + low SES.

    • ↵bResponse to therapy at the end of induction was grouped as follows: (i) patients with an M1 marrow (<5% blasts) at the end of induction; (ii) patients with an M2-M3 marrow (≥5% blasts) at the end of induction, but with M1 marrow on follow-up evaluation after additional therapy; (iii) patients who did not have a documented end of induction marrow, but the first marrow documented after initiation of treatment (>36 days) was M1 (“other”).

    • ↵cHigh-risk cytogenetic profile indicates presence of either: Philadelphia chromosome, MLL rearrangement and/or hypodiploidy.

  • Table 2.

    Multivariable hazard of relapse in AYA and children

    Relapse during therapya (all patients: n = 184)Relapse after completion of therapya (patients completed therapy: n = 119)
    HR (95% CI)PHR (95% CI)P
    Age group
     Child1.0 (—)—1.0 (—)—
     AYA10.5 (2.1–52.5)0.0047.7 (2.5–23.9)<0.001
    Duration of therapy
     Duration of maintenanceb1.0 (0.8–1.3)0.90.9 (0.8–0.9)<0.001
     Duration of consolidationb1.0 (0.8–1.3)0.90.9 (0.8–1.0)0.2
    Oncology service and therapy types
     Pediatric oncology + pediatric therapy1.0 (—)—1.0 (—)—
     Adult oncology + adult therapy2.5 (1.1–5.7)0.030.6 (0.2–1.8)0.3
     Mixed oncology + mixed therapy0.5 (0.2–1.8)0.30.23 (0.04–1.0)0.04
    Insurance and SES
     Private insurance + high SES1.0 (—)—1.0 (—)—
     Public insurance + low SES0.7 (0.3–1.5)0.36.2 (1.8–21.9)0.004
     Mixed profile0.9 (0.4–0.8)0.72.1 (0.5–8.3)0.3
    Race/ethnicity
     Non-Hispanic white1.0 (—)—1.0 (—)—
     Nonwhite race/ethnicity2.1 (1.1–4.0)0.030.6 (0.2–1.5)0.2
    Clinical trial enrollment
     Enrolled on clinical trial1.0 (—)—1.0 (—)—
     Not enrolled on clinical trial1.8 (0.9–3.5)0.090.6 (0.3–1.5)0.3
    Gender
     Female1.0 (—)—1.0 (—)—
     Male0.7 (0.4–1.3)0.33.3 (1.3–8.5)0.01
    Time
     Time in monthsb1.0 (0.8–1.3)0.81.0 (0.9–1.0)<0.001
    Clinical prognosticators
     WBC at diagnosis <50K1.0 (—)—1.0 (—)—
     WBC at diagnosis >50K1.6 (1.0–3.0)0.073.5 (1.4–8.8)0.007
     Precursor B-cell1.0 (—)—1.0 (—)—
     T-cell1.1 (0.6–2.1)0.80.2 (0.07–0.7)0.007
     No high-risk cytogenetics identified1.0 (—)—1.0 (—)—
     High-risk cytogenetic profile1.1 (0.5–2.3)0.80.5 (0.1–2.0)0.3
     M1 marrow at end of inductionc1.0 (—)—1.0 (—)—
     M2-M3 marrow at end of inductionc1.8 (0.9–4.0)0.12.0 (0.5–7.5)0.3
     CNS negative1.0 (—)—
     CNS positive4.9 (1.6–15.3)0.006
    • ↵aAdjusted discrete time survival analysis, modeling hazard of relapse with death due to nonrelapse causes and date of last contact as censoring events. Bolded values represent statistically significant findings. On-therapy model adjusted for AYA*time interaction.

    • ↵bThese variables were modeled as time-varying covariates. Months represents: (i) months from remission in the model calculating hazard of relapse on therapy; (ii) months from completion of therapy in the model calculating hazard of relapse after completing therapy. HRs represent each additional month of time from remission/completion of therapy, or each additional month of therapy.

    • ↵cPatients with M2-M3 marrows (≥5% blasts) at the end of induction were compared with patients who either (i) had M1 marrows (<5% blasts) at the end of induction or (ii) did not have a documented end of induction marrow, but the first marrow documented after initiation of treatment (>36 days) was M1.

  • Table 3.

    Multivariable hazard of relapse in AYA by time of relapse

    Relapse during therapya (all AYA: n = 93)Relapse after completion of therapya (AYA who completed therapy: n = 42)
    HR (95% CI)PHR (95% CI)P
    Duration of therapy
     Duration of maintenanceb0.9 (0.7–1.2)0.60.7 (0.6–0.8)<0.001
     Duration of consolidationb0.9 (0.7–1.2)0.60.8 (0.6–1.0)0.03
    Oncology service and therapy types
     Pediatric oncology + pediatric therapy1.0 (—)—1.0 (—)—
     Adult oncology + adult therapy1.9 (0.7–5.2)0.20.8 (0.1–4.7)0.8
     Mixed oncology + mixed therapy0.3 (0.1–1.5)0.20.3 (0.04–1.9)0.2
    Insurance and SES
     Private insurance + high SES1.0 (—)—1.0 (—)—
     Public insurance + low SES0.5 (0.2–1.4)0.26.8 (0.8–60.8)0.09
     Mixed profile0.6 (0.2–1.7)0.41.2 (0.1–12.5)0.9
    Race and ethnicity
     Non-Hispanic white1.0 (—)—1.0 (—)—
     Nonwhite race/ethnicity2.2 (1.0–4.8)0.050.2 (0.03–1.9)0.2
    Clinical trial enrollment
     Enrolled on clinical trial1.0 (—)—1.0 (—)—
     Not enrolled on clinical trial2.6 (1.0–6.3)0.041.1 (0.2–6.0)0.9
    Gender
     Female1.0 (—)—1.0 (—)—
     Male0.8 (0.4–1.7)0.61.3 (0.3–5.1)0.7
    Age
     Age, y1.00 (1.0–1.1)0.51.0 (0.9–1.1)1.0
    Time
     Time in monthsb1.1 (0.8–1.4)0.70.98 (0.96–1.0)0.03
    Clinical prognosticators
     WBC <50K1.0 (—)—1.0 (—)—
     WBC >50K1.6 (0.8–3.1)0.27.9 (1.6–38.8)0.01
     Precursor B cell1.0 (—)—1.0 (—)—
     T cell1.3 (0.6–2.6)0.50.3 (0.04–1.6)0.2
     No high-risk cytogenetics identified1.0 (—)—1.0 (—)—
     High-risk cytogenetic profile1.2 (0.6–2.6)0.7
     M1 marrow at end of inductionc1.0 (—)—1.0 (—)—
     M2-M3 marrow at end of inductionc2.0 (0.9–4.9)0.11.2 (0.2–6.6)0.9
     CNS negative1.0 (—)—
     CNS positive8.6 (2.1–35.0)0.003
    • ↵aAdjusted discrete time survival analysis, modeling hazard of relapse with death due to nonrelapse causes and date of last contact as censoring events. Bolded values represent statistically significant findings. On-therapy model adjusted for AYA*time interaction.

    • ↵bThese variables were modeled as time-varying covariates. Time at risk represents: (i) months from CR1 in the model calculating hazard of relapse on therapy; (ii) months from completion of therapy in the model calculating hazard of relapse after completing therapy. HRs represent each additional month of time from remission/completion of therapy, or each additional month of therapy.

    • ↵cPatients with M2-M3 marrows at the end of induction were compared with patients who either (i) had M1 marrows at the end of induction or (ii) did not have a documented end of induction marrow, but the first marrow documented after initiation of treatment (>36 days) was M1.

Additional Files

  • Figures
  • Tables
  • Supplementary Data

    • Supplementary Figure 1 - Consort Diagram of Final Evaluable Cohort
    • Supplementary Table 1 - Univariable Hazard of Relapse in Adolescents and Young Adults (AYA) and Children
    • Supplementary Figure 2 - Proportion of Patients per Age Group by Year at Diagnosis
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Cancer Epidemiology Biomarkers & Prevention: 27 (10)
October 2018
Volume 27, Issue 10
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Causes of Inferior Outcome in Adolescents and Young Adults with Acute Lymphoblastic Leukemia: Across Oncology Services and Regardless of Clinical Trial Enrollment
Julie A. Wolfson, Joshua S. Richman, Can-Lan Sun, Wendy Landier, Karen Leung, Eileen P. Smith, Margaret O’Donnell and Smita Bhatia
Cancer Epidemiol Biomarkers Prev October 1 2018 (27) (10) 1133-1141; DOI: 10.1158/1055-9965.EPI-18-0430

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Causes of Inferior Outcome in Adolescents and Young Adults with Acute Lymphoblastic Leukemia: Across Oncology Services and Regardless of Clinical Trial Enrollment
Julie A. Wolfson, Joshua S. Richman, Can-Lan Sun, Wendy Landier, Karen Leung, Eileen P. Smith, Margaret O’Donnell and Smita Bhatia
Cancer Epidemiol Biomarkers Prev October 1 2018 (27) (10) 1133-1141; DOI: 10.1158/1055-9965.EPI-18-0430
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