Treatment with a combination of ibrutinib and rituximab improved progression-free survival (PFS) over rituximab alone in patients with WaldenstrÃ¶m macroglobulinemia (WM), according to results from a phase III randomized trial presented at the 2018 ASCO Annual Meeting. This survival benefit was observed regardless of disease stage or genotype.
"This is a combination with a remarkable activity as far as PFS, it is well-tolerated, and it [may become] a new standard of care for patients with this disease," presenter Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens School of Medicine in Greece, said of the results, which were published simultaneously in The New England Journal of Medicine.
The prospective, randomized trial included 150 patients with symptomatic WM that was rituximab-sensitive (i.e., not refractory to last prior rituximab-based therapy or had not received rituximab within 12 months of study entry).
Participants were randomized to receive intravenous rituximab 375 mg/m2 once-weekly on weeks one through 4 and 17 through 20 with either ibrutinib 420 mg once-daily (arm A; n=75) or placebo (arm B; n=75).
Patient characteristics were similar among both arms: Median age was 70 years (range = 36-89 years) in arm A and 68 years (range = 39-85 years) in arm B, and one-third of patients were older than 75 years. Approximately one-third had a high International Prognostic Scoring System score, and 45 percent in each arm had previously untreated disease.
Ninety-three percent of patients in arm A completed treatment, while 71 percent in arm B completed treatment. Treatment discontinuation was related to progressive disease in seven patients (9%) and 33 patients (44%) in arms A and B, respectively, and to adverse events (AEs) in four patients (5%) and three patients (4%), respectively.
At a median follow-up of 26.5 months (range not provided), the median PFS was not reached in the ibrutinib plus rituximab cohort, compared with 20.3 months in the rituximab plus placebo cohort (ranges not reported; hazard ratio [HR] = 0.20; 95% CI 0.11- 0.38; p<0.0001). The 30-month PFS rates were 82 percent and 28 percent, respectively.
"Improved progression-free survival was seen across all prespecified subgroups, including age, prior history of treatment, baseline levels of immunoglobulin M (IgM), and – most importantly – different genotype," Dr. Dimopoulos said. "We know that ibrutinib has less activity [with respect to] response and progression-free survival in patients who experience mutations with MYD88 and CXCR4, but that was not the case [in this analysis]."
Hazard ratios for PFS in selected subgroups were:
- treatment-naÃ¯ve disease (HR=0.34; 95% CI 0.12-0.95)
- relapsed disease (HR=0.17; 95% CI 0.08-0.36)
- MYD88L265P/CXCR4WT mutation (HR=0.17; 95% CI 0.06-0.49)
- MYD88L265P/CXCR4WHIM mutation (HR=0.24; 95% CI 0.09-0.66)
- MYD88WT/CXCR4WT mutation (HR=0.21; 95% CI 0.04-1.1)
The 30-month overall survival rate was similar in both treatment arms (94% vs. 92%; p value not reported); this analysis included the 30 patients in the placebo arm who were allowed to cross over to single-agent ibrutinib.
Four patients died in the ibrutinib group, and six patients died in the placebo group. However, the overall, long-term survival data are immature.
Regarding the overall response rate (defined as a major response or better), Dr. Dimopoulos noted that there was "still significant activity of single-agent rituximab in these patients (47%), however the combination of ibrutinib and rituximab increases the response rate to 92 percent (p<0.0001). The major response rate (defined as a partial response or better) was also higher in the combination group (72% vs. 32%; p<0.0001).
The activity was rapid, he added, particularly in patients with high levels of IgM at baseline (â‰¥50 g/L): At week 9, mean IgM reduced 39 percent from baseline in arm A, and none of the patients required plasmapheresis.
The investigators observed more "significant and sustained" improvements in hemoglobin levels with ibrutinib plus rituximab, both in the entire patient population and in patients with baseline hemoglobin â‰¤11 g/dL: 73 percent versus 41 percent (p<0.0001) and 95 percent versus 56 percent (p<0.0001), respectively. "This is an important endpoint that affects patients' quality of life," Dr. Dimopoulos added, particularly because "anemia was one of the most common reasons for initiating therapy."
Rates of AEs were similar in each group: all patients experienced at least one AE, and 45 and 46 patients (60% and 61%) in arms A and B, respectively, experienced a grade â‰¥3 AE. The most common AEs included infusion-related reactions (32 [43%] and 44 [59%]), diarrhea (21 [28%] and 11 [15%]), and anemia (14 [19%] and 4 [5%]), respectively.
Dr. Dimopoulos stressed that the safety profile was manageable in the ibrutinib-rituximab group, even though median treatment duration was longer in the combination group (median = 25.8 months; range = 1.0-37.2 months) than in the placebo group (median = 15.5 months; range = 0.4-34.3 months).
The study is limited by its short duration of follow-up, and the preplanned analysis may have introduced potential bias.
The authors report financial relationships with Janssen and Roche.
Dimopoulos MA, Tedeschi A, Trotman J, et al. Randomized phase 3 trial of ibrutinib/ rituximab vs placebo/rituximab in WaldenstrÃ¶m's macroglobulinemia. Abstract #8003. Presented at the 2018 American Society of Clinical Oncology Annual Meeting, June 1, 2018; Chicago, IL.