After analyzing treatment patterns in chronic lymphocytic leukemia (CLL) (objective 1), we investigated the relative effectiveness of ibrutinib versus other commonly used treatments (objective 2) in patients with treatment-naïve and relapsed/refractory CLL, comparing patient-level data from two randomized registration trials with two real-world databases. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated using a multivariate Cox proportional hazards model, adjusted for differences in baseline characteristics. Rituximab-containing regimens were often prescribed in clinical practice. The most frequently prescribed regimens were fludarabine + cyclophosphamide + rituximab (FCR, 29.3%), bendamustine + rituximab (BR, 17.7%), and other rituximab-containing regimens (22.0%) in the treatment-naïve setting (n = 604), other non-FCR/BR rituximab-containing regimens (38.7%) and non-rituximab-containing regimens (28.5%) in the relapsed/refractory setting (n = 945). Adjusted HRs (95% CI) for progression-free survival (PFS) and overall survival (OS), respectively, with ibrutinib versus real-world regimens were 0.23 (0.14-0.37; p < 0.0001) and 0.40 (0.22-0.76; p = 0.0048) in the treatment-naïve setting, and 0.21 (0.16-0.27; p < 0.0001) and 0.29 (0.21-0.41; p < 0.0001) in the relapsed/refractory setting. When comparing real-world use of ibrutinib (n = 53) versus other real-world regimens in relapsed/refractory CLL (objective 3), adjusted HRs (95% CI) were 0.37 (0.22-0.63; p = 0.0003) for PFS and 0.53 (0.27-1.03; p < 0.0624) for OS. This adjusted analysis, based on nonrandomized patient data, suggests ibrutinib to be more effective than other commonly used regimens for CLL.

's Hertogenbosch The Netherlands

1st Department of Medicine Department of Hematology 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

4th Department of Internal Medicine Hematology University Hospital and Faculty of Medicine Charles University Hradec Králové Czech Republic

CEITEC Masaryk University Brno Czech Republic

Centre Hospitalier Lyon Sud Hospices Civils de Lyon Université Claude Bernard INSERM 1052 Pierre Bénite France

Department of Internal Medicine Hematology and Oncology University Hospital and Faculty of Medicine Masaryk University Brno Czech Republic

IQVIA Real World Insight Solutions London UK

Janssen Cilag GmbH Neuss Germany

Janssen Cilag Limited High Wycombe UK

Janssen Pharmaceutica NV Beerse Belgium

Janssen Pharmaceuticals Paris France

Janssen Sciences Dublin Ireland

University Hospital Olomouc Olomouc Czech Republic

University Hospital Pilsen Pilsen Czech Republic

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Ghielmini M, Vitolo U, Kimby E, Montoto S, Walewski J, Pfreundschuh M, Federico M, Hoskin P, McNamara C, Caligaris-Cappio F, Stilgenbauer S, Marcus R, Trneny M, Dreger P, Montserrat E, Dreyling M. ESMO guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) Ann Oncol. 2013;24(3):561–576. doi: 10.1093/annonc/mds517. PubMed DOI PMC

Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Lewis DR, Chen HS, Feuer EJ, Cronin KA (2016) SEER Cancer Statistics Review, 1975-2013, National Cancer Institute. https://seer.cancer.gov/csr/1975_2013/. Accessed 6 November 2017

Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers. Hematology Am Soc Hematol Educ Program. 2013;2013:158–167. doi: 10.1182/asheducation-2013.1.158. PubMed DOI

Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Dohner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101–1110. doi: 10.1056/NEJMoa1313984. PubMed DOI

Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grunhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jager U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Buhler A, Winkler D, Zenz T, Bottcher S, Ritgen M, Mendila M, Kneba M, Dohner H, Stilgenbauer S. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164–1174. doi: 10.1016/S0140-6736(10)61381-5. PubMed DOI

Dutch/Belgium HOVON CLL Working Group Dutch guidelines for the diagnosis and treatment of chronic lymphocytic leukaemia. Neth J Med. 2016;74(2):68–74. PubMed

Brown JR, Hallek MJ, Pagel JM. ASCO Educational Book. Alexandria, VA: American Society of Clinical Oncology; 2017. Chemoimmunotherapy versus targeted treatment in chronic lymphocytic leukemia: when, how long, how much, and in which combination? pp. e387–e398. PubMed

Zelenetz AD, Abramson JS, Advani RH, Andreadis CB, Byrd JC, Czuczman MS, Fayad L, Forero A, Glenn MJ, Gockerman JP, Gordon LI, Harris NL, Hoppe RT, Horwitz SM, Kaminski MS, Kim YH, LaCasce AS, Mughal TI, Nademanee A, Porcu P, Press O, Prosnitz L, Reddy N, Smith MR, Sokol L, Swinnen L, Vose JM, Wierda WG, Yahalom J, Yunus F. NCCN Clinical Practice Guidelines in Oncology: non-Hodgkin's lymphomas. J Natl Compr Cancer Netw. 2010;8(3):288–334. doi: 10.6004/jnccn.2010.0021. PubMed DOI

Zelenetz AD, Wierda WG, Abramson JS, Advani RH, Andreadis CB, Bartlett N, Bellam N, Byrd JC, Czuczman MS, Fayad LE, Glenn MJ, Gockerman JP, Gordon LI, Harris NL, Hoppe RT, Horwitz SM, Kelsey CR, Kim YH, Krivacic S, LaCasce AS, Nademanee A, Porcu P, Press O, Pro B, Reddy N, Sokol L, Swinnen L, Tsien C, Vose JM, Yahalom J, Zafar N, Dwyer MA, Naganuma M. Non-Hodgkin's lymphomas, version 1.2013. J Natl Compr Cancer Netw. 2013;11(3):257–272. doi: 10.6004/jnccn.2013.0037. PubMed DOI

Sant M, Allemani C, Tereanu C, De Angelis R, Capocaccia R, Visser O, Marcos-Gragera R, Maynadie M, Simonetti A, Lutz JM, Berrino F. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood. 2010;116(19):3724–3734. doi: 10.1182/blood-2010-05-282632. PubMed DOI

IMBRUVICA® (2019) [prescribing information]. Pharmacyclics LLC, Sunnyvale, CA, Janssen Biotech, Inc., Horsham, PA.

IMBRUVICA (2019) [summary of product characteristics]. Janssen Pharmaceutica NV, Beerse, Belguim.

Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O'Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425–2437. doi: 10.1056/NEJMoa1509388. PubMed DOI PMC

Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213–223. doi: 10.1056/NEJMoa1400376. PubMed DOI PMC

Eichhorst B, Robak T, Montserrat E, Ghia P, Hillmen P, Hallek M, Buske C, Guidelines Committee ESMO. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl 5):v78–v84. doi: 10.1093/annonc/mdv303. PubMed DOI

National Comprehensive Cancer Network (2018) NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines). Chronic lymphocytic leukemia/small lymphocytic leukemia, v5.2018. https://www.nccn.org/professionals/physician_gls/default.aspx. Accessed 18 July 2018

Wierda WG, Zelenetz AD, Gordon LI, Abramson JS, Advani RH, Andreadis CB, Bartlett N, Byrd JC, Caimi P, Fayad LE, Fisher RI, Glenn MJ, Habermann TM, Harris NL, Hernandez-Ilizaliturri F, Hoppe RT, Horwitz SM, Kaminski MS, Kelsey CR, Kim YH, Krivacic S, LaCasce AS, Martin MG, Nademanee A, Porcu P, Press O, Rabinovitch R, Reddy N, Reid E, Roberts K, Saad AA, Snyder ED, Sokol L, Swinnen LJ, Vose JM, Yahalom J, Dwyer MA, Sundar H. NCCN guidelines insights: chronic lymphocytic leukemia/small lymphocytic leukemia, version 1.2017. J Natl Compr Cancer Netw. 2017;15(3):293–311. doi: 10.6004/jnccn.2017.0030. PubMed DOI

Davids MS, Brown JR. Ibrutinib: a first in class covalent inhibitor of Bruton's tyrosine kinase. Future Oncol. 2014;10(6):957–967. doi: 10.2217/fon.14.51. PubMed DOI PMC

Itchaki G, Brown JR. Experience with ibrutinib for first-line use in patients with chronic lymphocytic leukemia. Ther Adv Hematol. 2018;9(1):3–19. doi: 10.1177/2040620717741861. PubMed DOI PMC

Shanafelt TD, Wang V, Kay NE, Hanson CA, O'Brien SM, Barrientos JC, Erba HP, Stone RM, Litzow MR, Tallman MS. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN Cancer Research Group (E1912) [ASH abstract] Blood. 2018;132:LBA–LB4. doi: 10.1182/blood-2018-120779. DOI

Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, Bartlett NL, Brander DM, Barr P, Rogers KA, Parikh SA, Coutre S, Hurria A, Lozanski G, Nattam S, Larson RA, Erba HP, Litzow MR, Owen C, Atkins J, Abramson JS, Little RF, Smith SE, Stone RM, Mandrekar SJ, Byrd JC. Ibrutinib alone or in combination with rituximab produces superior progression free survival (PFS) compared with bendamustine plus rituximab in untreated older patients with chronic lymphocytic leukemia (CLL): results of Alliance North American Intergroup Study A041202 [ASH abstract] Blood. 2018;132:6. doi: 10.1182/blood-2018-99-116653. DOI

Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Samoilova O, Novak J, Ben-Yehuda D, Strugov V, Gill D, Gribben JG, Hsu E, Zhou C, Clow F, James DF, Styles L, Flinn IW. Ibrutinib + obinutuzumab versus chlorambucil + obinutuzumab as first-line treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL): results from phase 3 iLLUMINATE [ASH abstract] Blood. 2018;132:691. doi: 10.1182/blood-2018-99-111370. DOI

U.S. Food & Drug Administration (2018) Framework for FDA’s real-world evidence program. https://www.fda.gov/media/120060/download. Accessed 27 August 2019

Berger ML, Sox H, Willke RJ, Brixner DL, Eichler HG, Goettsch W, Madigan D, Makady A, Schneeweiss S, Tarricone R, Wang SV, Watkins J, Daniel Mullins C. Good practices for real-world data studies of treatment and/or comparative effectiveness: recommendations from the joint ISPOR-ISPE Special Task Force on real-world evidence in health care decision making. Pharmacoepidemiol Drug Saf. 2017;26(9):1033–1039. doi: 10.1002/pds.4297. PubMed DOI PMC

Garside J, Healy N, Besson H, Hermans R, MacDougall F, Lestelle D, Diels J, Iraqi W. PHEDRA: using real-world data to analyze treatment patterns and ibrutinib effectiveness in hematological malignancies. J Comp Eff Res. 2018;7(1):29–38. doi: 10.2217/cer-2017-0046. PubMed DOI

Lin Y. Robust inference for responder analysis: innovative clinical trial design using a minimum p-value approach. Contemp Clin Trials Commun. 2016;3:65–69. doi: 10.1016/j.conctc.2016.04.001. PubMed DOI PMC

Robins JM, Hernan MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology. 2000;11(5):550–560. doi: 10.1097/00001648-200009000-00011. PubMed DOI

Hernan MA, Robins JM. Using big data to emulate a target trial when a randomized trial is not available. Am J Epidemiol. 2016;183(8):758–764. doi: 10.1093/aje/kwv254. PubMed DOI PMC

Brown JR, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre SE, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Thornton P, Caligaris-Cappio F, Delgado J, Montillo M, DeVos S, Moreno C, Pagel JM, Munir T, Burger JA, Chung D, Lin J, Gau L, Chang B, Cole G, Hsu E, James DF, Byrd JC. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018;32(1):83–91. doi: 10.1038/leu.2017.175. PubMed DOI PMC

O'Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, Sharman J, Wierda W, Jones J, Zhao W, Heerema NA, Johnson AJ, Luan Y, James DF, Chu AD, Byrd JC. Single-agent ibrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018;131(17):1910–1919. doi: 10.1182/blood-2017-10-810044. PubMed DOI PMC

Hansson L, Asklid A, Diels J, Eketorp-Sylvan S, Repits J, Soltoft F, Jager U, Osterborg A. Ibrutinib versus previous standard of care: an adjusted comparison in patients with relapsed/refractory chronic lymphocytic leukaemia. Ann Hematol. 2017;96(10):1681–1691. doi: 10.1007/s00277-017-3061-3. PubMed DOI PMC

Hillmen P, Fraser G, Jones J, Rule S, O’Brien S, Dilhuydy M, Jaeger U, Grosicki S, F. C. Sun S, Ninomoto J, Mahler M, Cheng M, Diels J, Clow F, Salman M, James D, Howes A, Chanan-Khan A. Comparing single-agent ibrutinib, bendamustine plus rituximab (BR) and ibrutinib plus BR in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): an indirect comparison of the RESONATE and HELIOS trials [ASH abstract] Blood. 2015;126(23):2944. doi: 10.1182/blood.V126.23.2944.2944. DOI

Ysebaert L, Aurran-Schleinitz T, Dartigeas C, Dilhuydy MS, Feugier P, Michallet AS, Tournilhac O, Dupuis J, Sinet P, Albrecht C, Cymbalista F. Real-world results of ibrutinib in relapsed/refractory CLL in France: early results on a large series of 428 patients. Am J Hematol. 2017;92(8):E166–E168. doi: 10.1002/ajh.24773. PubMed DOI

Winqvist M, Asklid A, Andersson PO, Karlsson K, Karlsson C, Lauri B, Lundin J, Mattsson M, Norin S, Sandstedt A, Hansson L, Osterborg A. Real-world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: data from 95 consecutive patients treated in a compassionate use program. A study from the Swedish Chronic Lymphocytic Leukemia Group. Haematologica. 2016;101(12):1573–1580. doi: 10.3324/haematol.2016.144576. PubMed DOI PMC

Mauro FR, Soddu S, Frustaci AM, Orsucci L, Motta M, Scarfo L, Zinzani PL, Falzetti F, Farina L, Marasca R, Cortelezzi A, Carlo-Stella C, Molica S, Coscia M, Zaja F, Laurenti L, de Fabritiis P, Gaidano G, Gobbi M, Tani M, Di Renzo N, Fazi P, Vignetti M, Cuneo A, Foà R. Outcome of patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) treated with ibrutinib within a named patient program (NPP) in Italy. a real-life retrospective study [ASH abstract] Blood. 2018;132:3147. doi: 10.1182/blood-2018-99-116653. DOI

Hillmen P, Diels J, Healy N, Iraqi W, Aschan J, Wildgust M. Ibrutinib for chronic lymphocytic leukemia: international experience from a named patient program. Haematologica. 2018;103(5):e204–e206. doi: 10.3324/haematol.2017.178798. PubMed DOI PMC

Robak T, Burger JA, Tedeschi A, Barr PM, Owen C, Bairey O, Hillmen P, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre SE, Quach H, Gaidano G, Maslyak Z, Stevens DA, Moreno C, Gill DS, Flinn IW, Gribben JG, Mokatrin A, Cheng M, Styles L, James DF, Kipps TJ, Ghia P. Single-agent ibrutinib versus chemoimmunotherapy regimens for treatment-naive patients with chronic lymphocytic leukemia: a cross-trial comparison of phase 3 studies. Am J Hematol. 2018;93(11):1402–1410. doi: 10.1002/ajh.25259. PubMed DOI PMC

Developing PRISM: A Pragmatic Institutional Survey and Bench Marking Tool to Measure Digital Research Maturity of Cancer Centers