Randomized Trial of Ibrutinib versus Ibrutinib plus Rituximab in Patients with CLL

Conference Correspondent - ASH 2017 - CLL

Single-agent ibrutinib (ibr) is currently approved as monotherapy for the treatment of chronic lymphocytic leukemia (CLL), both in treatment-naïve and relapsed patients. Results from a phase 2 study combining ibr with rituximab (rtx) in high-risk patients with CLL demonstrated encouraging high overall response rates (ORRs; 95%).1 At ASH 2017, the authors reported on an open-label, randomized, single-center trial of ibr versus ibr plus rtx in 206 patients with relapsed or treatment-naïve CLL to determine whether rtx provides added benefit to ibr therapy.2

Patients were randomized to receive ibr (n = 102) or ibr plus rtx (Ib+R, n = 104); the study included patients with relapsed CLL and treatment-naïve patients with high-risk disease (del17p or TP53 mutation, n = 27). Patients were treated with oral ibr 420 mg daily until adverse events, disease progression, or death precluded further therapy. Patients randomized to Ib+R received rtx during the first 6 months of treatment (375 mg/m2 weekly during the first 4 weeks [cycle 1], then monthly for cycles 2-6), in addition to ibr. The primary end point was progression-free survival (PFS); secondary end points included ORR per revised International Working Group on CLL criteria, safety, and tolerability.

Of the 188 evaluable patients in the study, 37% had del(17p) or TP53 mutation, 20% had del(11q), 72% had unmutated IGHV, and 38% had advanced-stage disease (Rai stage 3-4). After a median observation time of 25.2 and 22.7 months, 20 (21%) patients on the ibr arm and 26 (28%) patients on the Ib+R arm achieved complete remission (CR; P = .309); partial remissions were achieved in 72 (77%) and 68 (72%) patients receiving ibr or Ib+R, respectively, accounting for an ORR of 98% for ibr-, and 100% for Ib+R-treated patients.

Bone marrow flow cytometry assessments for minimal residual disease (MRD) at the time of last follow-up showed a significantly lower level of residual CLL cells in Ib+R-treated patients (median, 4.9% CLL cells) when compared with ibr-treated patients (17.1%; P = .002). CR with MRD negativity was observed in 5 patients treated with Ib+R and in 1 patient treated with ibr.

The median time to normalization of the absolute lymphocyte count (≤4.0 K/μL) was significantly shorter in Ib+R‒treated patients compared with ibr-treated patients (3.0 months vs 8.9 months; P <.001). The median time to achieve CR was also significantly shorter in Ib+R-treated patients (11.5 months, vs 21.1 months in the ibr-treated patients; P = .032); however, there was not a significant difference in PFS between the patients treated with ibr and Ib+R during the observation period (91.2% vs 90.4%; P = .788).

Among the 56 patients who came off study (23 from ibr and 33 from Ib+R), toxicities were the most common cause for therapy discontinuation (n = 28); 8 patients had disease progression (5 with ibr and 3 on the Ib+R arm); disease transformation was reported in 3 patients, occurring between 11 and 16 months on treatment. The most frequently reported treatment-related adverse events were similarly distributed in both arms.

The authors concluded that the addition of rtx to ibr in relapsed and high-risk CLL patients did not improve PFS, but patients treated with Ib+R reached their remissions significantly faster and achieved lower MRD levels. Given these results, single-agent ibr should remain the standard-of-care therapy in CLL. The addition of rtx can be considered in high-risk patients in whom a faster response is desired.


  1. Burger JA, et al. Lancet Oncol. 2014;15:1090-1099.
  2. Burger JA, et al. ASH 2017. Abstract 427.
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