Ibrutinib-rituximab combo improves PFS in patients with Waldenström’s macroglobulinaemia
The addition of the BTK* inhibitor ibrutinib to the monoclonal antibody rituximab resulted in improvement in progression-free survival (PFS) in treatment-naïve and relapsed patients with Waldenström’s macroglobulinaemia (WM) compared with placebo, according to results from the iNNOVATE (PCYC-1127)** trial presented at EHA 2018.
A total of 150 patients (median age 69 years) who were nonrefractory to prior rituximab-based therapies were randomized 1:1 to receive oral ibrutinib 420 mg once daily or placebo until evidence of disease progression, combined with intravenous rituximab at a standard dose of 375 mg/m2 on day 1 of weeks 1–4 and 17–20. Of these, 136 patients had mutation data available (MYD88L265P and CXCR4WHIM in 85 percent and 36 percent, respectively). Thirty placebo recipients received ibrutinib at the time of progression. [EHA 2018, abstract S852]
At a median follow-up of 26.5 months, 30-month PFS rates were 82 percent and 28 percent in the ibrutinib and placebo arms, respectively. There was a significant PFS improvement favouring the ibrutinib-rituximab combination over placebo independent of MYD88/CXCR4 genotypes (not reached vs 20.3, hazard ratio, 0.20, 95 percent confidence interval, 0.11–0.38; p<0.0001).
“We would need several years to reach median PFS,” said Dr Meletios Dimopoulos from the National Kapodistrian University of Athens School of Medicine in Athens, Greece. “[Nonetheless,] the combination of ibrutinib and rituximab improved PFS regardless of prognostic or genotypic factors,” he added.
PFS improvements were also consistent in all subgroups (HR, 0.34 and 0.17 for treatment-naïve and relapsed patients, respectively), as well as in those who had specific genotypes (HR, 0.17, 0.24, and 0.21 for MYD88L265P/CXCR4WT, MYD88L265P/CXCR4WHIM, and MYD88WT/CXCR4WT, respectively).
Despite previous reports showing shorter PFS and response to ibrutinib among patients with wild-type MYD88 or CXCR4 mutations vs those without these genotypes, the current findings demonstrated that the ibrutinib-rituximab combination essentially abrogated these results, Dimopoulos said.
Response rates (RR) were also significantly higher in the ibrutinib vs the placebo arm (72 percent vs 32 percent; p<0.0001 and 92 percent vs 47 percent; p<0.0001 for major and overall RR, respectively).
There was also a higher rate of sustained haemoglobin improvement in the ibrutinib vs the placebo arm (73 percent vs 41 percent; p<0.0001). “This is actually a very significant parameter for patients’ quality of life,” Dimopoulos pointed out.
Overall, the ibrutinib-rituximab combination regimen should be considered a standard therapeutic option for patients with newly diagnosed or previously treated WM, said Dimopoulos.
At the media briefing, Dr Anton Hagenbeek from the Academic Medical Center at the University of Amsterdam, the Netherlands, who was not affiliated with the study, commented that this combination regimen is a ‘major step forward’ in the treatment of WM, which is an incurable type of lymphoma in the elderly.
According to Dimopoulos, there is still room for improvement in WM treatment. “We would like to develop regimens that may deepen the response and clear the bone marrow as … BTK inhibitors do not really clear the bone marrow.”
Incorporating a third agent such as venetoclax, which has a significant [activity] in WM, or the proteasome inhibitor carfilzomib, which is very active in WM and has been reported to have a significant activity in patients with CXCR4 mutations, might be warranted especially for those with indolent disease, he added. “[We could develop] a triplet regimen that could be given for a fixed duration of time … [and] avoid the administration of ibrutinib for years in these patients.”