TY - JOUR
T1 - Measurable residual disease does not preclude prolonged progression-free survival in CLL treated with ibrutinib
AU - Wang, Xin Victoria
AU - Hanson, Curtis A.
AU - Tschumper, Renee C.
AU - Lesnick, Connie E.
AU - Braggio, Esteban
AU - Paietta, Elisabeth M.
AU - O'Brien, Susan
AU - Barrientos, Jacqueline C.
AU - Leis, Jose Francisco
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 - Erba, Harry
AU - Stone, Richard
AU - Litzow, Mark R.
AU - Tallman, Martin S.
AU - Shanafelt, Tait D.
AU - Kay, Neil E.
N1 - Funding Information:
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: U10CA180820, U10CA180794, U10CA180821, U10CA180888, UG1CA189821, UG1CA189859, UG1CA189863, UG1CA190140, UG1CA232760, UG1CA233180, UG1CA233230, UG1CA233253, UG1CA233290, and UG1CA233339; and by National Institutes of Health National Cancer Institute grant R01CA193541 (principal investigators Neil Kay and Tait Shanafelt). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Mentions of trade names, commercial products, or organizations do not imply endorsement by the US government.
Funding Information:
Conflict-of-interest disclosure: R.S. reports grants and personal fees from AbbVie and Agios; grants from Arog; and personal fees from Actinium, Astellas, Argenx, AstraZeneca, Biolinerx, Daiichi-Sankyo, Elevate, Gemoab, Hoffman LaRoche, Janssen, Macrogenics, Novartis, Otsuka, Pfizer, Syndax, Syntrix, Syros, Takeda, and Trovagene outside the submitted work. E.B. reports consulting fees from DASA. S.E.C. has received institutional research funding from AbbVie, Acerta, Gilead, Janssen, Pharmacyclics, and Takeda; has served on the Data Safety Monitoring Committee (DSMC) for Beigene and the Clinical Trial Steering Committee for Acerta; has been a consultant for AbbVie, Adaptive, Astellas, AstraZeneca, Genentech, Gilead, Janssen, and Pharmacyclics; has received honoraria from Janssen, Pharmacyclics, (CME accredited) Imedex, and Medscape and travel expenses from AbbVie, Beigene, Genentech, Janssen, and Pharmacyclics; and has served as an expert witness for Genentech. P.M.B. has been a consultant for Pharmacyclics, AbbVie, Genentech, Gilead, AstraZeneca, Bayer, Merck, Celgene/BMS, Morphosys, TG Therapeutics, and Seattle Genetics. T.D.S. has received research support from Pharmacyclics, Genentech, and AbbVie. N.E.K. has served on the advisory boards of AbbVie, AstraZeneca, Cytomx Therapy, Dava Oncology, Juno Therapeutics, Oncotracker, Pharmacyclics, and Targeted Oncology and on the DSMCs of Agios Pharm, AstraZeneca, BMS-Celgene, Cytomx Therapeutics, Morpho-sys, and Rigel; and has received research funding from AbbVie, Acerta Pharma, Bristol Meyer Squib, Celgene, MEI Pharma, Pharmacyclics, Sunesis, TG Therapeutics, and Tolero Pharmaceuticals. A.R.M. has received research support from TG Therapeutics, Pharmacyclics, AbbVie, Johnson and Johnson, Acerta, AZ, Regeneron, DTRM Bio Pharma, Sunesis, Loxo Oncology Adaptive; and has served on advisory boards and the DSMCs and as a consultant for TG Therapeutics, Pharmacyclics, AbbVie, Johnson and Johnson, Acerta, AZ, DTRM Bio Pharma, Sunesis, and Adaptive. M.S.T. has received research funding from AbbVie, Cellerant, Orsenix, ADC Therapeutics, Biosight, Glycomimetics, Rafael Pharmaceuticals, and Amgen; has served on the advisory boards of AbbVie, BioLineRx, Daiichi-Sankyo, Orsenix, KAHR, Rigel, Nohla, Delta Fly Pharma, Tetraphase, Oncolyze, Jazz Pharma, Roche, Biosight, and Novartis; and has received royalties from UpToDate. H.E. has received research funding from AbbVie, Agios, Amgen, Daiichi Sankyo, Forma, Forty Seven/Gilead, Glycomimetics, ImmunoGen, Jazz, Macrogenics, and Novartis. S.O. has received research support from Kite, Regeneron, and Gilead; has received research support and served as a consultant for Gilead, Pharmacyclics, TG Therapeutics, Pfizer, and Sunesis; and has been a consultant to 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.C.B. has received research funding from Oncternal and Velosbio and has been a consultant to AbbVie, AstraZeneca, Pharmacyclics/AbbVie, and Kite/Gilead. X.V.W., C.A.H., R.C.T., M.R.L., A.K.S., A.F.C., E.M.P., C.E.L., R.C.T., M.P.M., J.F.L., and C.C.Z. declare no competing financial interests.
Funding Information:
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: U10CA180820, U10CA180794, U10CA180821, U10CA180888, UG1CA189821, UG1CA189859, UG1CA189863, UG1CA190140, UG1CA232760, UG1CA233180, UG1CA233230, UG1CA233253, UG1CA233290, and UG1CA233339; and by National Institutes of Health National Cancer Institute grant R01CA193541 (principal investigators Neil Kay and Tait Shanafelt).
Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/12/30
Y1 - 2021/12/30
N2 - E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus 6 cycles of rituximab (IR) to 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (<1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4%, and 8.6% at 3, 12, 24, and 36 months for FCR, and significantly lower at 7.9%, 4.2%, and 3.7% at 12, 24, and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24, and 36 months was associated with longer progression-free survival (PFS) in the FCR arm, with hazard ratios (MRD detectable/MRD undetectable) of 4.29 (95% confidence interval [CI], 1.89-9.71), 3.91 (95% CI, 1.39-11.03), 14.12 (95% CI, 1.78-111.73), and not estimable (no events among those with undetectable MRD), respectively. In the IR arm, patients with detectable MRD did not have significantly worse PFS compared with those in whom MRD was undetectable; however, PFS was longer in those with MRD levels <10−1 than in those with MRD levels above this threshold. Our observations provide additional support for the use of MRD as a surrogate end point for PFS in patients receiving FCR. In patients on indefinite ibrutinib-based therapy, PFS did not differ significantly by undetectable MRD status, whereas those with MRD <10−1 tended to have longer PFS, although continuation of ibrutinib would very likely be necessary to maintain treatment efficacy.
AB - E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus 6 cycles of rituximab (IR) to 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (<1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4%, and 8.6% at 3, 12, 24, and 36 months for FCR, and significantly lower at 7.9%, 4.2%, and 3.7% at 12, 24, and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24, and 36 months was associated with longer progression-free survival (PFS) in the FCR arm, with hazard ratios (MRD detectable/MRD undetectable) of 4.29 (95% confidence interval [CI], 1.89-9.71), 3.91 (95% CI, 1.39-11.03), 14.12 (95% CI, 1.78-111.73), and not estimable (no events among those with undetectable MRD), respectively. In the IR arm, patients with detectable MRD did not have significantly worse PFS compared with those in whom MRD was undetectable; however, PFS was longer in those with MRD levels <10−1 than in those with MRD levels above this threshold. Our observations provide additional support for the use of MRD as a surrogate end point for PFS in patients receiving FCR. In patients on indefinite ibrutinib-based therapy, PFS did not differ significantly by undetectable MRD status, whereas those with MRD <10−1 tended to have longer PFS, although continuation of ibrutinib would very likely be necessary to maintain treatment efficacy.
UR - http://www.scopus.com/inward/record.url?scp=85121933464&partnerID=8YFLogxK
U2 - 10.1182/blood.2020010146
DO - 10.1182/blood.2020010146
M3 - Article
C2 - 34407545
AN - SCOPUS:85121933464
VL - 138
SP - 2810
EP - 2827
JO - Blood
JF - Blood
SN - 0006-4971
IS - 26
ER -