Combo Improves Outcomes in Waldenström Macroglobulinemia

Adding Ibrutinib to Rituximab Improves PFS Over Rituximab Alone

Waldenström macroglobulinemia (WM) is an uncommon plasma-cell disorder, characterized by overproduction of serum immunoglobulin M (IgM). While there is no standard of care for WM, the anti-CD20 monoclonal antibody rituximab is a common treatment for both treatment-naïve and previously treated patients. Furthermore, based on results from a phase II study in previously treated patients with WM, the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib was approved in 2015 for the treatment of WM.

In 150 symptomatic patients with WM, the randomized phase III iNNOVATE trial compared the combination of ibrutinib and rituximab to rituximab alone. Meletios Dimopoulous, MD, PhD (University of Athens, Athens, Greece), presented results from a preplanned interim analysis of the iNNOVATE trial at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting and during the 23rd Congress of the European Hematology Association (EHA). Results were published in The New England Journal of Medicine simultaneously with the ASCO presentation.

At a median follow-up of 26.5 months, the addition of ibrutinib to rituximab had significantly improved progression-free survival (PFS), compared to rituximab and placebo (not reached vs 20.3 months; HR 0.2, P<.001). The 30-month PFS rate was 82% in patients receiving ibrutinib plus rituximab, compared to 28% in patients receiving rituximab alone. The PFS benefit of the ibrutinib and rituximab combination was seen in all patients, regardless of treatment line (treatment naïve or previously treated) and across different MYD88 and CXCR4 genotypes. The overall response rate (ORR) was significantly higher in patients receiving ibrutinib (92% vs 47%; P<.0001), with a greater proportion of patients achieving a major response (ie, partial response or better; 72% vs 32%; P<.0001). Sustained increases in hemoglobin level occurred in more patients treated with ibrutinib plus rituximab than with rituximab alone (73% vs 41%; P<.001).

The 30-month overall survival (OS) rate was 94% in patients receiving ibrutinib plus rituximab and 92% in patients receiving rituximab alone. Dr Dimopoulous explained that 30 patients (40%) in the control arm crossed over to receive single-agent ibrutinib after disease progression, which may have impacted OS analysis.

The adverse event (AE) profile for the combination of ibrutinib and rituximab was consistent with the known safety profile of these agents, and there were no unexpected toxicities. There were similar rates of grade 3/4 treatment-related AEs in both treatment arms (60% vs 61%). Grade ≥3 AEs occurring more commonly in patients treated with ibrutinib plus rituximab included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%). Both IgM flare and infusion-related reactions were more common in patients receiving rituximab alone.

In his conclusion, Dr Dimopolous indicated that these results support the combination of ibrutinib and rituximab as the new standard of care for patients with Waldenström macroglobulinemia, noting the impressive improvement in PFS and manageable toxicity profile.


J Clin Oncol. 2018;36(suppl): Abstract 8003.

N Engl J Med. 2018;378:2399-2410.

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