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, 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

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.

© 2022 by The American Society of Hematology.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
PFS from discontinuation of ibrutinib. Includes patients who discontinued ibrutinib for reasons other than progression or death and known to be progression-free at the time of discontinuation.
Figure 2.
Figure 2.
PFS. (A) PFS among all patients; (B) PFS among patients with unmutated IGHV; (C) PFS among patients with mutated IGHV; (D) PFS for patients remaining on ibrutinib. Patients who went off ibrutinib for AEs or reasons other than progression are censored at the time of ibrutinib discontinuation.
Figure 3.
Figure 3.
PFS by CLL IPI risk group. (A) PFS by CLL IPI risk group for FCR-treated patients; (B) PFS by CLL IPI risk group for IR-treated patients; (C) PFS by treatment arm within each CLL IPI risk group.
Figure 4.
Figure 4.
OS comparison for IR vs FCR arms.

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