Results from the Final Analysis of the Phase 3 iNNOVATE Study: Nursing Experience with Patients Receiving Ibrutinib plus Rituximab for Waldenström’s Macroglobulinemia

December 2021 Vol 12, No 12
Kate Mimken, NP-C
Colorado Blood Cancer Institute, Denver, CO
Tolu Adewuya, MMedSci, PhD, CCRC
Winship Cancer Institute of Emory University, Atlanta, GA
Bernhard Hauns, MD, PhD
Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA
Israel Arango-Hisijara, MD
Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA
Leonard T. Heffner, MD
Winship Cancer Institute of Emory University, Atlanta, GA
Jeffrey V. Matous, MD
Colorado Blood Cancer Institute, Denver, CO

Background: Ibrutinib is the only oral once-daily Bruton tyrosine kinase inhibitor widely approved as either a single-agent therapy or in combination with rituximab for patients with Waldenström’s macroglobulinemia (WM) across all lines of therapy. In earlier data from the phase 3 iNNOVATE study, ibrutinib showed superior progression-free survival (PFS) when combined with rituximab compared with placebo-rituximab in patients with WM1; real-world outcomes in patients with WM treated with ibrutinib are generally consistent with clinical trial results.2 As ibrutinib is used as a continuous therapy, oncology nurses may provide important continuous treatment-related support to maximize patient outcomes.

Objectives: To provide recommendations based on oncology nurse experience for patient education and adverse event (AE) management and to present long-term results from the final analysis of the randomized portion of iNNOVATE.

Methods: In iNNOVATE, a total of 150 patients with WM were randomly assigned 1:1 to receive once-daily ibrutinib 420 mg or placebo in combination with rituximab (375 mg/m2/week IV at weeks 1-4 and 17-20).

Results: At the final analysis, the median follow-up was 50 (range: 0.5+ to 63) months. PFS was longer with ibrutinib-rituximab versus placebo-rituximab (median PFS: ibrutinib-rituximab, not reached; placebo-rituximab, 20 months; P <.0001). Compared with placebo-rituximab (33/75, 44%), superior overall response rates were observed for patients treated with ibrutinib-rituximab (69/75, 92%; P <.0001), regardless of prior treatment or MYD88 or CXCR4 genotype. A greater proportion of patients receiving ibrutinib-rituximab versus placebo-rituximab had sustained hemoglobin improvement (77% vs 43%; P <.0001). Among patients receiving ibrutinib-rituximab, minimal increases in rates of common grade 3/4 AEs (occurring in ≥10% of patients) were observed after 24 additional months of follow-up since the primary analysis: anemia (+1%), hypertension (+1%), neutropenia (+4%), and atrial fibrillation (+4%). With a median treatment duration of 48 months, the safety profile of ibrutinib-rituximab remained manageable. Of 12 patients with grade 3/4 atrial fibrillation, 9 (75%) remained on treatment; no other ibrutinib discontinuations due to common grade 3/4 AEs occurred. There were 68 (45%) patients who remained on ibrutinib after study closure, including 23/35 patients who crossed over from placebo-rituximab to receive single- agent ibrutinib.

Per the nurse authors’ experience, oncology nurses can encourage continuous ibrutinib treatment by informing patients on the importance of adherence to therapy. Specifically, nurses can help patients identify and manage AEs and can review written materials with patients to address AE-related concerns. Together, these actions may help patients receive optimal treatment benefits from continuous ibrutinib.

Conclusions: In the longest follow-up to date, ibrutinib-rituximab showed ongoing superior PFS regardless of prior treatment or genotype and benefit across clinical outcomes in patients with WM compared with placebo-rituximab. Due to their direct interaction with patients, oncology nurses can provide patient education and timely support for AE management to maximize the clinical benefit of therapy.


  1. Dimopoulos MA, Tedeschi A, Trotman J, et al. Phase 3 trial of ibrutinib plus rituximab in Waldenström’s macroglobulinemia. N Engl J Med. 2018;378:2399-2410.
  2. Abeykoon JP, Zanwar S, Ansell SM, et al. Ibrutinib monotherapy outside of clinical trial setting in Waldenström macroglobulinaemia: practice patterns, toxicities and outcomes. Br J Haematol. 2020;188:394-403.
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