Could ibrutinib become the new therapy standard for Waldenström's macroglobulinemia (WM)?

In patients with Waldenström's macroglobulinemia (WM), the additional administration of ibrutinib to rituximab can reduce the risk of progression or death by relatively 80% compared to rituximab-only treatment.

Results on reduced mortality risk through the additional administration of ibrutinib presented

In patients with Waldenström's macroglobulinemia (WM), the additional administration of ibrutinib to rituximab can reduce the risk of progression or death by relatively 80% compared to rituximab-only treatment.

Meletios A. Dimopoulos from the Faculty of Medicine at the University of Athens presented the results of iNNOVATE Phase-3 study pre-planned interim analysis at the ASCO (American Society of Clinical Oncology) Annual Meeting 2018 (1). In parallel to the event, these results were published in the New England Journal of Medicine (2).

Waldenström's macroglobulinemia (WM) is a rare disease that belongs to indolent lymphomas. It mainly affects older people and is slightly more common in men than in women. The clinical symptoms are mainly based on the consequences of bone marrow infiltration by lymphoplasmacytic lymphoma with suppression of normal hematopoiesis and hypersecretion of monoclonal immunoglobulin M (IgM). Therapy is usually initiated in patients suffering from anemia, hyperviscosity, fatigue or other symptoms.

The role of BTK inhibitor ibrutinib in Waldenström's macroglobulinemia

More recently, up to 90% of WM patients have been diagnosed with an MYD88-L265P mutation, which constitutively activates the NF-kB pathway via Bruton's tyrosine kinase (BTK). Ibrutinib (Imbruvica®), an oral inhibitor of BTK, has been available for the first time since 2014 and is already approved in Europe for WM after the pretreatment or in first-line therapy if the patients are unsuitable for chemoimmunotherapy. The CD20 inhibitor rituximab has long been a standard therapy for the disease.

The Phase 3 iNNOVATE study now randomized Efficacy and tolerability of ibrutinib plus rituximab and placebo plus rituximab compared in 150 patients with WM in first-line therapy or recurrent disease. All patients received 375 mg/m² of i.v. rituximab once a week for 4 weeks and these 4 doses were repeated after a break of 3 months. Randomized, all patients continuously took ibrutinib 420 mg/day (n = 75) or placebo (n = 75). Primary endpoints were progression-free survival (PFS), secondary endpoints included response rates and sustained hematological improvement, the median time to next treatment and overall survival.

The results of a predefined interim analysis, which was planned after 50 progression events or deaths, were now presented and published.

Significant extension of the PFS

The two groups were comparable in demographic parameters. After a median follow-up of 26.5 months, the additional administration of ibrutinib significantly improved PFS from 20.3 months under rituximab alone, to a currently unknown level (hazard ratio 0.20, p < 0.0001). This means an 80% reduction in the relative risk of progression or death. PFS rates after 30 months were 82% with ibrutinib and 28% without ibrutinib. ibrutinib has significantly improved PFS compared to rituximab monotherapy in all subgroups in patients with therapies (HR 0.34), recurrent disease (HR 0.17) and patients with MYD88-L265P and CXCR4-WHIM mutations (HR 0.24).

Overall response rates were significantly higher under the combination of 92% than 47% under rituximab monotherapy (p < 0.0001). Ibrutinib led to a faster decrease in serum IgM levels. In addition, hemoglobin levels continued to improve in 73% of patients with ibrutinib/rituximab and in only 41% (p < 0.001) with rituximab alone, "a very important factor for patient well-being," Dimopoulos said. After 30 months, 94% of patients still lived in the ibrutinib group and 92% in the rituximab group. At the time of the interim analysis, 75% of patients continued ibrutinib-rituximab treatment.

Severe adverse events of Grade 3 or higher occurred in a similar number of patients, 60% ibrutinib/rituximab and 61% rituximab, with median treatment with ibrutinib for 25.8 months and placebo for 15.5 months. There were no fatal side effects in the ibrutinib arm, 3 patients died in the rituximab arm as a result of adverse effects. Atrial fibrillation (AFib) occurred in 15% of ibrutinib patients and 3% of the peer group was affected by this side effect. However, patients over 75 years of age were particularly affected by this undesirable effect. Only 5 and 4% of patients in the ibrutinib and rituximab arms discontinued the study due to side effects.

Conclusion: a Remarkable activity of ibrutinib

"This combination has a remarkable activity and should become a new therapeutic standard for Waldenström's macroglobulinemia," concludes Dimopoulos. Discussant Craig C. Hofmeister, from the Emory University School of Medicine in Atlanta, said: "The response rates were great and there were no unexpected toxicities”. Hofmeister pointed out that the response to ibrutinib was “particularly good in patients with proven MYD88 mutations” and concluded: "Ibrutinib + rituximab are a benefit in MYD88-mutated patients". However, adverse effects such as atrial fibrillation and infections need closer monitoring.


  1. Dimopoulos MA, et al. Randomized phase 3 trial of ibrutinib/rituximab vs placebo/rituximab in Waldenström's macroglobulinemia. 2018 ASCO Annual Meeting, Chicago, June 1-5, 2018, Abstract LBA8003.
  2. Dimopoulos MA, et al. Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia. N Engl J Med. published online on June 1, 2018.