Long-term outcomes for ibrutinib–rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial

Tait D. Shanafelt; Xin Victoria Wang; Curtis A. Hanson; Elisabeth M. Paietta; Susan O'Brien; Jacqueline Barrientos; Diane F. Jelinek; Esteban Braggio; Jose F. Leis; Cong Christine Zhang; Steven E. Coutre; Paul M. Barr; Amanda F. Cashen; Anthony R. Mato; Avina K. Singh; Michael P. Mullane; Richard F. Little; Harry Erba; Richard M. Stone; Mark Litzow; Martin Tallman; Neil E. Kay

doi:10.1182/blood.2021014960

Long-term outcomes for ibrutinib–rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial

Tait D. Shanafelt^*, Xin Victoria Wang, Curtis A. Hanson, Elisabeth M. Paietta, Susan O'Brien, Jacqueline Barrientos, Diane F. Jelinek, Esteban Braggio, Jose F. Leis, Cong Christine Zhang, Steven E. Coutre, Paul M. Barr, Amanda F. Cashen, Anthony R. Mato, Avina K. Singh, Michael P. Mullane, Richard F. Little, Harry Erba, Richard M. Stone, Mark LitzowMartin Tallman, Neil E. Kay

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

145 Scopus citations

Abstract

Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib–rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.

Original language	English (US)
Pages (from-to)	112-120
Number of pages	9
Journal	Blood
Volume	140
Issue number	2
DOIs	https://doi.org/10.1182/blood.2021014960
State	Published - Jul 14 2022

Funding

Conflict-of-interest disclosure: T.D.S. reports receiving grant support from Pharmacyclics, AbbVie, and Genentech; and holds a patent (US14/292 075) on green tea extract epigallocatechin gallate in combination with chemotherapy for chronic lymphocytic leukemia. N.E.K. reports serving on the advisory board for AbbVie, AstraZeneca, Beigene, Behring, Cytomx Therapy, Dava Oncology, Janssen, Juno Therapeutics, Oncotracker, Pharmacyclics, and Targeted Oncology; serves on the DSMC (Data Safety Monitoring Committee) for Agios Pharm, AstraZeneca, BMS–Celgene, Cytomx Therapeutics, Janssen, Morpho-sys, and Rigel; and has received research funding from AbbVie, Acerta Pharma, Bristol Myers Squibb, Celgene, Genentech, MEI Pharma, Pharmacyclics, Sunesis, TG Therapeutics, and Tolero Pharmaceuticals. A.R.M. receives research support from TG Therapeutics, Pharmacyclics, AbbVie, Johnson and Johnson, Acerta, AZ, Regeneron, DTRM BioPharma, Sunesis, Loxo Oncology Adaptive; and advisory/consultancy/DSMB for TG Therapeutics, Pharmacyclics, AbbVie, Johnson and Johnson, Acerta, AZ, DTRM BioPharma, Sunesis, and Adaptive. S.O. receives research support from Kite, Regeneron, and Gilead; consultant and research support from Gilead, Pharmacyclics, TG Therapeutics, Pfizer, and Sunesis; consultant for Amgen, Astellas, Celgene, GSK, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verstem, Eisai, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, and Merck. J.B. receives research funding from Oncternal and Velosbio; consultant for AbbVie, AstraZeneca, Pharmacyclics/AbbVie, and Kite/Gilead; grant support and advisory board fees from Pharmacyclics-AbbVie; and lecture fees and travel support from Janssen, Gilead Sciences, and Genentech. E.B. reports consulting fees from DASA. S.E.C. receives funds as follows: institutional research funding from AbbVie, Acerta, Gilead, Janssen, Pharmacyclics, Takeda; Data Safety Monitoring Committee for Beigene; Clinical Trial Steering Committee for Acerta; consultancy from AbbVie, Adaptive, Astellas, AstraZeneca, Genentech, Gilead, Janssen, and Pharmacyclics; honoraria from Janssen, Pharmacyclics, (CME accredited) Imedex, and Medscape; travel expenses from AbbVie, Beigene, Genentech, Janssen, and Pharmacyclics; and expert witness for Genentech. P.M.B. consulted for Pharmacyclics, AbbVie, Genentech, Gilead, AstraZeneca, Bayer, Merck, Celgene/BMS, Morphosys, TG Therapeutics, and Seattle Genetics. A.F.C. reports serving on the advisory board for SecuraBio and ADC Therapeutics and receiving research funding from SecuraBio. A.R.M. receives grant support, consulting fees, fees for serving on a data and safety monitoring board, and advisory board fees from TG Therapeutics; grant support, consulting fees, and advisory board fees from Pharmacyclics, Johnson & Johnson, AbbVie, and AstraZeneca; grant support from Regeneron; fees for serving on a data and safety monitoring board and advisory board fees from Celgene; grant support and advisory board fees from Sunesis Pharmaceuticals and Loxo Oncology; and lecture fees, fees for continuing medical education events and other events from prIME Oncology. H.E. receives research funding from AbbVie, Agios, Amgen, Daiichi Sankyo, Forma, Forty Seven/Gilead, Glycomimetics, ImmunoGen, Jazz, Macrogenics, and Novartis; member of advisory boards for AbbVie, Agios, Astellas, Celgene/BMS, Daiichi Sankyo, Genentech, Glycomimetics, Incyte, Jazz, Kura Oncology, Novartis, Takeda, and Trillium; speakers bureau for AbbVie, Agios, Amgen Celgene/BMS, Incyte, Jazz, and Novartis; financial or material support from AbbVie (Chair, Independent Review Committee for VIALE A and VIALE C) and Celgene/BMS (Chair, AML Repository Study). M.T. receives research funding from AbbVie, Cellerant, Orsenix, ADC Therapeutics, Biosight, Glycomimetics, Rafael Pharmaceuticals, and Amgen; member of advisory board for AbbVie, BioLineRx, Daiichi-Sankyo, Orsenix, KAHR, Rigel, Nohla, Δ Fly Pharma, Tetraphase, Oncolyze, Jazz Pharma, Roche, Biosight, and Novartis; and receives royalties from UpToDate. R.M.S. reports grants and personal fees from AbbVie, Agios, and Novartis; grants from Arog; personal fees from Actinium, Argenx, Astellas, AstraZeneca, Biolinerx, Celgene, Daiichi-Sankyo, Elevate, Gemoab, Janssen, Jazz, Macrogenics, Otsuka, Pfizer, Hoffmann La Roche, Stemline, Syndax, Syntrix, Syros, Takeda, and Trovagene outside the submitted work. M.L. receives grant support and consulting fees from Amgen; grant support from Astellas Pharma, AbbVie, Actinium Pharmaceuticals, Novartis, and Pluristem Therapeutics; and consulting fees from Sanofi and NewLink Genetics. The remaining authors declare no competing financial interests. This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer and Mitchell D. Schnall, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180794, U10CA180821, U10CA180820, U10CA180888, UG1CA189859, UG1CA189863, UG1CA190140, UG1CA232760, UG1CA233180, UG1CA233230, UG1CA233253, UG1CA233290, and UG1CA233339. Correlative studies were supported by CA193541. The study was also supported in part by Pharmacyclics, Inc. (a subsidiary of AbbVie).

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

Access to Document

10.1182/blood.2021014960

Cite this

Shanafelt, T. D., Wang, X. V., Hanson, C. A., Paietta, E. M., O'Brien, S., Barrientos, J., Jelinek, D. F., Braggio, E., Leis, J. F., Zhang, C. C., Coutre, S. E., Barr, P. M., Cashen, A. F., Mato, A. R., Singh, A. K., Mullane, M. P., Little, R. F., Erba, H., Stone, R. M., ... Kay, N. E. (2022). Long-term outcomes for ibrutinib–rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood, 140(2), 112-120. https://doi.org/10.1182/blood.2021014960

@article{d4037dbfafa84a5fb3eb4bc4bcd94908,

title = "Long-term outcomes for ibrutinib–rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial",

abstract = "Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib–rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-na{\"i}ve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.",

author = "Shanafelt, {Tait D.} and Wang, {Xin Victoria} and Hanson, {Curtis A.} and Paietta, {Elisabeth M.} and Susan O'Brien and Jacqueline Barrientos and Jelinek, {Diane F.} and Esteban Braggio and Leis, {Jose F.} and Zhang, {Cong Christine} and Coutre, {Steven E.} and Barr, {Paul M.} and Cashen, {Amanda F.} and Mato, {Anthony R.} and Singh, {Avina K.} and Mullane, {Michael P.} and Little, {Richard F.} and Harry Erba and Stone, {Richard M.} and Mark Litzow and Martin Tallman and Kay, {Neil E.}",

note = "Publisher Copyright: {\textcopyright} 2022 American Society of Hematology",

year = "2022",

month = jul,

day = "14",

doi = "10.1182/blood.2021014960",

language = "English (US)",

volume = "140",

pages = "112--120",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

number = "2",

}

Shanafelt, TD, Wang, XV, Hanson, CA, Paietta, EM, O'Brien, S, Barrientos, J, Jelinek, DF, Braggio, E, Leis, JF, Zhang, CC, Coutre, SE, Barr, PM, Cashen, AF, Mato, AR, Singh, AK, Mullane, MP, Little, RF, Erba, H, Stone, RM, Litzow, M, Tallman, M & Kay, NE 2022, 'Long-term outcomes for ibrutinib–rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial', Blood, vol. 140, no. 2, pp. 112-120. https://doi.org/10.1182/blood.2021014960

TY - JOUR

T1 - Long-term outcomes for ibrutinib–rituximab and chemoimmunotherapy in CLL

T2 - updated results of the E1912 trial

AU - Shanafelt, Tait D.

AU - Wang, Xin Victoria

AU - Hanson, Curtis A.

AU - Paietta, Elisabeth M.

AU - O'Brien, Susan

AU - Barrientos, Jacqueline

AU - Jelinek, Diane F.

AU - Braggio, Esteban

AU - Leis, Jose F.

AU - Zhang, Cong Christine

AU - Coutre, Steven E.

AU - Barr, Paul M.

AU - Cashen, Amanda F.

AU - Mato, Anthony R.

AU - Singh, Avina K.

AU - Mullane, Michael P.

AU - Little, Richard F.

AU - Erba, Harry

AU - Stone, Richard M.

AU - Litzow, Mark

AU - Tallman, Martin

AU - Kay, Neil E.

PY - 2022/7/14

Y1 - 2022/7/14

N2 - Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib–rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.

AB - Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib–rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.

UR - http://www.scopus.com/inward/record.url?scp=85134354519&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85134354519&partnerID=8YFLogxK

U2 - 10.1182/blood.2021014960

DO - 10.1182/blood.2021014960

M3 - Article

C2 - 35427411

AN - SCOPUS:85134354519

SN - 0006-4971

VL - 140

SP - 112

EP - 120

JO - Blood

JF - Blood

IS - 2

ER -

Long-term outcomes for ibrutinib–rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this