Combo Improves Outcomes in Waldenstrom's Macroglobulinema

Pam Harrison

June 07, 2018

The combination of ibrutinib (Imbruvica, Pharmacyclics) plus rituximab (Rituxan, Genentech) dramatically extends progression-free survival (PFS) over rituximab alone in patients with Waldenstrom's macroglobulinema (WM), a rare form of B-cell lymphoma, according results from the iNNOVATE study.

"We found that the combination of ibrutinib plus rituximab resulted in significantly better efficacy over rituximab alone in producing rapid and durable responses, with substantially longer durations of PFS, both among patients who had received previous treatment and among those with recurrent disease," say the authors, led by Meletios Dimopoulos, MD, National and Kapodistrian University of Athens School of Medicine, Greece.

"We conclude that the addition of ibrutinib to rituximab represents a viable treatment approach for patients with Waldenstrom's macroglobulinema, both among those who have received no previous therapy and among those with disease recurrence, regardless of prognostic or genotypic factors," they conclude.

The study was funded by the manufacturers of ibrutinib. It was published online June 1 in the New England Journal of Medicine and was presented at the American Society of Clinical Oncology (ASCO) 2018 annual meeting.

Big Achievement

When asked by Medscape Medical News to comment on the new results, Adam Olszewski, MD, Lifespan Cancer Institute at Rhode Island Hospital in Providence, said he felt this was an "achievement," primarily because it is the first really large, phase 3 trial ever carried out in WM and that the combination of ibrutinib and rutiximab significantly improved PFS over rituximab alone.

"However, even though there was a dramatic improvement in PFS, there was no difference in overall survival between the two treatment arms," he cautioned.

The main drawback of ibrutinib is that it is extremely expensive and the duration of therapy has not been defined, he added.

"Treatment also has no end once ibrutinib is initiated, so it's an open-ended, long-term, costly treatment," he elaborated.

In contrast, many regimens used in the treatment of WM lead to remission in more than 80% of cases, and treatment can be terminated after only a few months, so the cost is much lower, Olszewski explained.

"The role of ibrutinib will likely be clarified in the future," he suggested.

"Nevertheless, this study will likely strongly influence practice in the US and perhaps elsewhere, although access to ibrutinib across the world may differ," Olszewski suggested.

Study Details

The trial involved 150 patients with WM who were randomly assigned to receive either oral ibrutinib 420 mg once a day or placebo until disease progression or unacceptable toxicity.

Both groups also received intravenous rituximab at a dose of 375 mg/m2, with infusions given at weeks 1 to 4 and again at weeks 17 to 20.

The mean age of the cohort was 69 years; about one third of patients were aged 75 years or older.

Slightly fewer than half of patients (45%) were treatment-naive; the median number of prior therapies among those with relapsed disease was two.

The majority of those who had been previously treated had received rituximab, the investigators point out.

Mutational status at study entry was not known for all 150 patients, but among those whose mutational status was known, the MYD88 L265P genotype was present in 85% of the cohort, and the CXCR4 genotype, which confers resistance to ibrutinib, was present in 36% of the group overall.

The most common reasons for initiating treatment were fatigue, anemia, and constitutional symptoms. Treatment was initiated in accordance with consensus guidelines.

Primary Endpoint: PFS at 30 Months

"The 30-month progression-free survival rate was 82% in the ibrutinib-rituximab group and 28% in the placebo-rituximab group...for an 80% lower risk of progression or death in the ibrutinib-rituximab group (P < .001)," the investigators report.

PFS rates were higher for those who received the combination of ibrutinib plus rituximab compared with those who received rituximab alone for both treatment-naive and previously treated patients, as well as for those with and those without the MYD88 or CXCR4 mutation.

The investigators explain that the MYD88 L265P mutation triggers the growth of malignant cells through the Bruton tyrosine kinase and hematopoetic-cell kinase pathways, both of which are inhibited by ibrutinib.

Table. PFS Rates at 24 Months in Prespecified Subgroups

  Combination Ibrutinib + Rituximab Rituximab Alone
No prior therapy 84% 59%
Previously treated, with disease recurrence 80% 22%
MYD88 present, CXCR4 absent (30-mo PFS rate) 86% 33%
Both MYD88/CXC4 present (30-mo PFS rate) 80% 29%
Neither MYD88 or CXCR4 present 80% 21%


For patients with either high-, intermediate-, or low-risk scores on the International Prognostic Scoring System for Waldenstrom's Macroglobulinema, higher rates of PFS were observed among patients treated with the combination compared with those who were treated with rituximab alone.

Secondary Endpoints

At 30 months, 94% of patients were still alive in the combination arm; for patients treated with rituximab alone, 92% were still alive at 30 months. The median duration of overall survival had not been reached in either group at study endpoint.

The investigators also documented significantly higher response rates among those treated with the combination compared with those treated with rituximab alone with respect to very good partial responses or partial responses, at 72% vs 32%, respectively (P < .001). Overall response rates were 92% and 47%, respectively (P < .001).

Again, robust responses to the combination were observed both in patients with the MYD88/CXCR4 genotypes and in those without.

The investigators note that patients received ibrutinib for a mean duration of almost 26 months, whereas those who received rituximab alone were treated for a median of 15.5 months, so safety data represented a longer period for the combination group.

Diarrhea, arthralgia, and nausea were more common in the combination arm than in the rituximab-alone arm. IgM flare, infusion-related reactions, fatigue, asthenia, anemia, and headache were all more common in the rituximab-alone group.

"The most common...adverse events that occurred more frequently with ibrutinib-rituximab than with placebo-rituximab included hypertension (13% vs 4%) and atrial fibrillation (12% vs 1%)," the investigators state; "those that occurred less frequently included anemia (11% vs 17%) and infusion-related reactions (1% vs 16%)," they add.

Discontinuation rates were low and were similar for both treatment groups.

The study was funded by Pharmacyclics and Janssen Research and Development. Dr Dimopoulos has received personal fees from Amgen, Takeda, Janssen, and Celgene. Dr Olszewski has received research funding from Spectrum Pharmaceuticals and Genetech.

American Society of Clinical Oncology (ASCO) 2018. Abstract 8003, presented June 1, 2018.

N Eng J Med. Published online June 1, 2018. Full text

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