ASCO 2018: Ibrutinib–Rituximab Improves Waldenström’s Macroglobulinemia PFS

Adding ibrutinib to first- or later-line rituximab therapy extends progression-free survival for patients with Waldenström’s macroglobulinemia

medwireNews: iNNOVATE study findings point to a significant improvement in progression-free survival (PFS) for patients with Waldenstrom’s macroglobulinemia who receive a combination of ibrutinib and rituximab versus rituximab alone.

The phase III trial findings for the Bruton’s tyrosine kinase inhibitor plus the CD20 inhibitor rituximab were presented at the ASCO Annual Meeting 2018 in Chicago, Illinois, USA, and simultaneously published in The New England Journal of Medicine.

Meletios Dimopoulos, from the National and Kapodistrian University of Athens, Alexandra Hospital in Greece, and co-authors believe that the combination “represents a viable treatment approach for patients with Waldenström’s macroglobulinemia, both among those who have received no previous therapy and among those with disease recurrence, regardless of prognostic or genotypic factors.”

The primary endpoint of PFS at 30 months was 82% for the 75 patients randomly assigned to receive ibrutinib 420 mg/day alongside rituximab infusion at a dose of 375 mg/m2 of body-surface area during weeks 1 to 4 and 17 to 20.

This was significantly higher than the 28% rate for the 75 patients given placebo plus rituximab, giving a significant hazard ratio (HR) for disease progression or death of 0.20.

The benefit of ibrutinib–rituximab was seen across the subgroups, including in patients who had previously achieved remission using a median of two agents (HR=0.17) and in those with treatment-naïve disease (HR=0.34). And response to the combination regimen did not depend on prognostic score, or the MYD88 or CXCR4 genotype, the researchers say.

Overall survival at 30 months was 94% with ibrutinib–rituximab versus 92% with placebo–rituximab. The researchers note, however, that the median value was not reached at this time in either group and 30 patients in the control arm transferred to combination therapy after confirmed disease progression.

Patients given ibrutinib–rituximab were significantly more likely to achieve a major response to treatment – defined as a complete, very good partial or partial response – than those given placebo–rituximab, at 72% versus 32%.

In particular, the investigators highlight the rate of very good partial response with ibrutinib–rituximab, at 23% versus just 4% in the control arm, and the “robust response” found in patients regardless of MYD88 genotype.

Meletios Dimopoulos et al note that patients using ibrutinib–rituximab were significantly more likely than controls to experience a sustained increase in haemoglobin level (73 vs 41%), which they say

“allowed for amelioration of anemia and fatigue, which are among the most common reasons for initiating treatment.”

Ibrutinib was used for a median of 25.8 months and placebo for 15.5 months but the rate of discontinuation because of side effects was a comparable 5% and 4%, respectively.

The most common adverse events with combination treatment were infusion-related diarrhoea, arthralgia and nausea; ibrutinib-rituximab was associated with higher rates of grade 3 or more severe atrial fibrillation (12 vs 1%) and hypertension (13 vs 4%) but lower rates of infusion reactions (1 vs 16%) and immunoglobulin M (IgM) flare of any grade (8 vs 47%).

“The rapid reduction in IgM levels, especially in patients with high IgM levels at baseline, indicated that the addition of ibrutinib to rituximab can prevent IgM flare”, the researchers comment.

But they add that “[a]dditional analyses after longer-term follow-up will help to determine the risk of lymphoproliferative disorders with this regimen.”



Dimopoulos MA, Tedeschi A, Trotman J, et al. Phase 3 trial of ibrutinib plus rituximab in Waldenström’s macroglobulinemia . N Engl J Med; Advance online publication 1 June 2018.
DOI: 10.1056/NEJMoa1802917

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