Adding ibrutinib to rituximab improves long-term outcomes in patients with Waldenstrom’s macroglobulinemia (WM), according to final results from the phase 3 iNNOVATE trial.

These results, published in the Journal of Clinical Oncology,1 showed superior responses and progression-free survival (PFS) with the combination over rituximab alone.

The trial ( Identifier: NCT02165397) enrolled 150 patients with previously treated or treatment-naïve WM. The patients were randomly assigned to receive ibrutinib plus rituximab (75 patients) or placebo plus rituximab (75 patients).

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Baseline characteristics were generally well balanced between the treatment arms. The median age at baseline was 70 years (range, 36-89 years) in the ibrutinib arm and 68 years (range, 39-85 years) in the placebo arm. Roughly half of patients in each arm (55%) had received at least 1 prior systemic treatment for WM.

The primary analysis, at a median follow-up of 26.5 months, demonstrated superior PFS and overall response rate (ORR) with ibrutinib plus rituximab, independent of patient genotype.2

At the final analysis, the median follow-up was 50 months. PFS and ORR remained superior with ibrutinib plus rituximab, and these benefits were observed irrespective of patient genotype or prior treatment status.

The median PFS was not reached in the ibrutinib-rituximab arm and was 20.3 months in the placebo-rituximab arm (hazard ratio [HR], 0.25; 95% CI, 0.15-0.42; P <.0001).

The ORR (minor response or better) was 92% in the ibrutinib-rituximab arm and 44% in the placebo-rituximab arm. The major response rate (partial response or better) was 76% and 31%, respectively (P <.0001). 

The depth of response to ibrutinib-rituximab increased over time. The major response rate increased from 72% at month 24 to 76% at month 60.

The median time to next treatment was significantly longer with ibrutinib-rituximab than with placebo-rituximab — not reached and 18 months, respectively (P <.0001).

The median overall survival was not reached in either treatment arm (HR, 0.81; 95% CI, 0.33-1.99; P =.6430).

In the ibrutinib-rituximab arm, the most common grade 3 or higher treatment-emergent adverse events of clinical interest were infections and infestations, anemia, atrial fibrillation, and hypertension. In general, the prevalence of these events decreased over time.

Disclosures: This research was supported by Pharmacyclics LLC. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


  1. Buske C, Tedeschi A, Trotman J, et al. Ibrutinib plus rituximab versus placebo plus rituximab for Waldenström’s Macroglobulinemia: Final analysis from the randomized phase III iNNOVATE study. J Clin Oncol. Published online October 4, 2021. doi:10.1200/JCO.21.00838
  2. Dimopoulos MA, Tedeschi A, Trotman J, et al. Phase 3 trial of ibrutinib plus rituximab in Waldenstrom’s macroglobulinemia. N Engl J Med. 2018;378(25):2399-2410. doi:10.1056/NEJMoa1802917