Diagnosis-to-treatment interval is an important clinical factor in newly diagnosed diffuse large B-cell lymphoma and has implication for bias in clinical trials

Matthew J. Maurer, Hervé Ghesquières, Brian K. Link, Jean Philippe Jais, Thomas Matthew Habermann, Carrie A Thompson, Corinne Haioun, Cristine Allmer, Patrick Bruce Johnston, Richard Delarue, Ivana Micallef, Frederic Peyrade, David J. Inwards, Nicolas Ketterer, Umar Farooq, Olivier Fitoussi, William R. Macon, Thierry J. Molina, Sergei Syrbu, Andrew L Feldman & 8 others Susan L Slager, George J. Weiner, Stephen Maxted Ansell, James R Cerhan, Gilles A. Salles, Thomas Elmer Witzig, Hervé Tilly, Grzegorz S Nowakowski

Research output: Contribution to journalArticle

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Abstract

Purpose Selection bias in clinical trials has consequences for scientific validity and applicability of study results to the general population. There is concern that patients with clinically aggressive disease may not have enrolled in recent diffuse large B-cell lymphoma (DLBCL) trials due to the consent process and the inability to delay therapy for eligibility evaluation. We have examined the diagnosisto-treatment interval (DTI) and its association with clinical factors and outcome in a clinic-based observational cohort of patients with DLBCL from the United States. Validation of results was performed in an independent, clinical trial-based cohort from Europe. Patients and Methods Patients were prospectively enrolled in the University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource (MER; N = 986) or the Lymphoma Study Association (LYSA) LNH-2003 clinical trials program (N = 1, 444). All patients received anthracyclinebased immunochemotherapy at initial diagnosis. Associations of DTI with clinical factors and outcome were examined. Outcome was assessed using event-free survival at 24 months from diagnosis (EFS24). Results Median (range) DTI was 15 days (0 to 155 days in the MER and 23 days (0 to 215 days) in LYSA. Shorter DTI was strongly associated with adverse clinical factors, including elevated lactate dehydrogenase levels, poor performance status, B symptoms, and higher International Prognostic Index in both cohorts (all P <.001). Longer DTI was associated with improved EFS24 in both the MER (per-week odds ratio, 0.80; 95% CI, 0.74 to .0.87) and LYSA (per-week odds ratio, 0.90; 95% CI, 0.86 to 0.94); association with EFS24 remained significant after adjustment for International Prognostic Index. Conclusion DTI is strongly associated with prognostic clinical factors and outcome in newly diagnosed DLBCL. DTI should be reported in all clinical trials of newly diagnosed DLBCL and future trials should take steps to avoid selection bias due to treatment delay.

Original languageEnglish (US)
Pages (from-to)1603-1610
Number of pages8
JournalJournal of Clinical Oncology
Volume36
Issue number16
DOIs
StatePublished - Jun 1 2018

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Lymphoma, Large B-Cell, Diffuse
Clinical Trials
Lymphoma
Therapeutics
Selection Bias
Odds Ratio
Molecular Epidemiology
L-Lactate Dehydrogenase
Disease-Free Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Diagnosis-to-treatment interval is an important clinical factor in newly diagnosed diffuse large B-cell lymphoma and has implication for bias in clinical trials. / Maurer, Matthew J.; Ghesquières, Hervé; Link, Brian K.; Jais, Jean Philippe; Habermann, Thomas Matthew; Thompson, Carrie A; Haioun, Corinne; Allmer, Cristine; Johnston, Patrick Bruce; Delarue, Richard; Micallef, Ivana; Peyrade, Frederic; Inwards, David J.; Ketterer, Nicolas; Farooq, Umar; Fitoussi, Olivier; Macon, William R.; Molina, Thierry J.; Syrbu, Sergei; Feldman, Andrew L; Slager, Susan L; Weiner, George J.; Ansell, Stephen Maxted; Cerhan, James R; Salles, Gilles A.; Witzig, Thomas Elmer; Tilly, Hervé; Nowakowski, Grzegorz S.

In: Journal of Clinical Oncology, Vol. 36, No. 16, 01.06.2018, p. 1603-1610.

Research output: Contribution to journalArticle

Maurer, MJ, Ghesquières, H, Link, BK, Jais, JP, Habermann, TM, Thompson, CA, Haioun, C, Allmer, C, Johnston, PB, Delarue, R, Micallef, I, Peyrade, F, Inwards, DJ, Ketterer, N, Farooq, U, Fitoussi, O, Macon, WR, Molina, TJ, Syrbu, S, Feldman, AL, Slager, SL, Weiner, GJ, Ansell, SM, Cerhan, JR, Salles, GA, Witzig, TE, Tilly, H & Nowakowski, GS 2018, 'Diagnosis-to-treatment interval is an important clinical factor in newly diagnosed diffuse large B-cell lymphoma and has implication for bias in clinical trials', Journal of Clinical Oncology, vol. 36, no. 16, pp. 1603-1610. https://doi.org/10.1200/JCO.2017.76.5198
Maurer, Matthew J. ; Ghesquières, Hervé ; Link, Brian K. ; Jais, Jean Philippe ; Habermann, Thomas Matthew ; Thompson, Carrie A ; Haioun, Corinne ; Allmer, Cristine ; Johnston, Patrick Bruce ; Delarue, Richard ; Micallef, Ivana ; Peyrade, Frederic ; Inwards, David J. ; Ketterer, Nicolas ; Farooq, Umar ; Fitoussi, Olivier ; Macon, William R. ; Molina, Thierry J. ; Syrbu, Sergei ; Feldman, Andrew L ; Slager, Susan L ; Weiner, George J. ; Ansell, Stephen Maxted ; Cerhan, James R ; Salles, Gilles A. ; Witzig, Thomas Elmer ; Tilly, Hervé ; Nowakowski, Grzegorz S. / Diagnosis-to-treatment interval is an important clinical factor in newly diagnosed diffuse large B-cell lymphoma and has implication for bias in clinical trials. In: Journal of Clinical Oncology. 2018 ; Vol. 36, No. 16. pp. 1603-1610.
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abstract = "Purpose Selection bias in clinical trials has consequences for scientific validity and applicability of study results to the general population. There is concern that patients with clinically aggressive disease may not have enrolled in recent diffuse large B-cell lymphoma (DLBCL) trials due to the consent process and the inability to delay therapy for eligibility evaluation. We have examined the diagnosisto-treatment interval (DTI) and its association with clinical factors and outcome in a clinic-based observational cohort of patients with DLBCL from the United States. Validation of results was performed in an independent, clinical trial-based cohort from Europe. Patients and Methods Patients were prospectively enrolled in the University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource (MER; N = 986) or the Lymphoma Study Association (LYSA) LNH-2003 clinical trials program (N = 1, 444). All patients received anthracyclinebased immunochemotherapy at initial diagnosis. Associations of DTI with clinical factors and outcome were examined. Outcome was assessed using event-free survival at 24 months from diagnosis (EFS24). Results Median (range) DTI was 15 days (0 to 155 days in the MER and 23 days (0 to 215 days) in LYSA. Shorter DTI was strongly associated with adverse clinical factors, including elevated lactate dehydrogenase levels, poor performance status, B symptoms, and higher International Prognostic Index in both cohorts (all P <.001). Longer DTI was associated with improved EFS24 in both the MER (per-week odds ratio, 0.80; 95{\%} CI, 0.74 to .0.87) and LYSA (per-week odds ratio, 0.90; 95{\%} CI, 0.86 to 0.94); association with EFS24 remained significant after adjustment for International Prognostic Index. Conclusion DTI is strongly associated with prognostic clinical factors and outcome in newly diagnosed DLBCL. DTI should be reported in all clinical trials of newly diagnosed DLBCL and future trials should take steps to avoid selection bias due to treatment delay.",
author = "Maurer, {Matthew J.} and Herv{\'e} Ghesqui{\`e}res and Link, {Brian K.} and Jais, {Jean Philippe} and Habermann, {Thomas Matthew} and Thompson, {Carrie A} and Corinne Haioun and Cristine Allmer and Johnston, {Patrick Bruce} and Richard Delarue and Ivana Micallef and Frederic Peyrade and Inwards, {David J.} and Nicolas Ketterer and Umar Farooq and Olivier Fitoussi and Macon, {William R.} and Molina, {Thierry J.} and Sergei Syrbu and Feldman, {Andrew L} and Slager, {Susan L} and Weiner, {George J.} and Ansell, {Stephen Maxted} and Cerhan, {James R} and Salles, {Gilles A.} and Witzig, {Thomas Elmer} and Herv{\'e} Tilly and Nowakowski, {Grzegorz S}",
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T1 - Diagnosis-to-treatment interval is an important clinical factor in newly diagnosed diffuse large B-cell lymphoma and has implication for bias in clinical trials

AU - Maurer, Matthew J.

AU - Ghesquières, Hervé

AU - Link, Brian K.

AU - Jais, Jean Philippe

AU - Habermann, Thomas Matthew

AU - Thompson, Carrie A

AU - Haioun, Corinne

AU - Allmer, Cristine

AU - Johnston, Patrick Bruce

AU - Delarue, Richard

AU - Micallef, Ivana

AU - Peyrade, Frederic

AU - Inwards, David J.

AU - Ketterer, Nicolas

AU - Farooq, Umar

AU - Fitoussi, Olivier

AU - Macon, William R.

AU - Molina, Thierry J.

AU - Syrbu, Sergei

AU - Feldman, Andrew L

AU - Slager, Susan L

AU - Weiner, George J.

AU - Ansell, Stephen Maxted

AU - Cerhan, James R

AU - Salles, Gilles A.

AU - Witzig, Thomas Elmer

AU - Tilly, Hervé

AU - Nowakowski, Grzegorz S

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Purpose Selection bias in clinical trials has consequences for scientific validity and applicability of study results to the general population. There is concern that patients with clinically aggressive disease may not have enrolled in recent diffuse large B-cell lymphoma (DLBCL) trials due to the consent process and the inability to delay therapy for eligibility evaluation. We have examined the diagnosisto-treatment interval (DTI) and its association with clinical factors and outcome in a clinic-based observational cohort of patients with DLBCL from the United States. Validation of results was performed in an independent, clinical trial-based cohort from Europe. Patients and Methods Patients were prospectively enrolled in the University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource (MER; N = 986) or the Lymphoma Study Association (LYSA) LNH-2003 clinical trials program (N = 1, 444). All patients received anthracyclinebased immunochemotherapy at initial diagnosis. Associations of DTI with clinical factors and outcome were examined. Outcome was assessed using event-free survival at 24 months from diagnosis (EFS24). Results Median (range) DTI was 15 days (0 to 155 days in the MER and 23 days (0 to 215 days) in LYSA. Shorter DTI was strongly associated with adverse clinical factors, including elevated lactate dehydrogenase levels, poor performance status, B symptoms, and higher International Prognostic Index in both cohorts (all P <.001). Longer DTI was associated with improved EFS24 in both the MER (per-week odds ratio, 0.80; 95% CI, 0.74 to .0.87) and LYSA (per-week odds ratio, 0.90; 95% CI, 0.86 to 0.94); association with EFS24 remained significant after adjustment for International Prognostic Index. Conclusion DTI is strongly associated with prognostic clinical factors and outcome in newly diagnosed DLBCL. DTI should be reported in all clinical trials of newly diagnosed DLBCL and future trials should take steps to avoid selection bias due to treatment delay.

AB - Purpose Selection bias in clinical trials has consequences for scientific validity and applicability of study results to the general population. There is concern that patients with clinically aggressive disease may not have enrolled in recent diffuse large B-cell lymphoma (DLBCL) trials due to the consent process and the inability to delay therapy for eligibility evaluation. We have examined the diagnosisto-treatment interval (DTI) and its association with clinical factors and outcome in a clinic-based observational cohort of patients with DLBCL from the United States. Validation of results was performed in an independent, clinical trial-based cohort from Europe. Patients and Methods Patients were prospectively enrolled in the University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource (MER; N = 986) or the Lymphoma Study Association (LYSA) LNH-2003 clinical trials program (N = 1, 444). All patients received anthracyclinebased immunochemotherapy at initial diagnosis. Associations of DTI with clinical factors and outcome were examined. Outcome was assessed using event-free survival at 24 months from diagnosis (EFS24). Results Median (range) DTI was 15 days (0 to 155 days in the MER and 23 days (0 to 215 days) in LYSA. Shorter DTI was strongly associated with adverse clinical factors, including elevated lactate dehydrogenase levels, poor performance status, B symptoms, and higher International Prognostic Index in both cohorts (all P <.001). Longer DTI was associated with improved EFS24 in both the MER (per-week odds ratio, 0.80; 95% CI, 0.74 to .0.87) and LYSA (per-week odds ratio, 0.90; 95% CI, 0.86 to 0.94); association with EFS24 remained significant after adjustment for International Prognostic Index. Conclusion DTI is strongly associated with prognostic clinical factors and outcome in newly diagnosed DLBCL. DTI should be reported in all clinical trials of newly diagnosed DLBCL and future trials should take steps to avoid selection bias due to treatment delay.

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