To the editor

Marginal zone lymphomas (MZL) are the third most common B cell non-Hodgkin lymphoma (NHL) comprising 7% of all NHLs [1,2,3]. Ibrutinib was FDA-approved for relapsed or refractory (R/R) MZL based on phase II clinical trial that showed an overall response rate (ORR) of 48% [4]. In the recently updated long-term follow-up of this study, the ORR was 58% with a median duration of response (DOR) of 27.6 months [5]. However, factors associated with response (or lack thereof) to ibrutinib in R/R MZL in clinical practice are largely unknown. Hence, we sought to evaluate characteristics predictive of ibrutinib failure in R/R MZL and describe the outcomes of patients on ibrutinib therapy in a “real-world” setting.

In this multicenter retrospective cohort study, we included adult patients (18 years or older) with R/R MZL who received ibrutinib monotherapy between 2010 and 2019 at 25 US medical centers. The study population was divided into 3 groups: "ibrutinib responders”—patients who achieved a complete response (CR) or partial response (PR) to ibrutinib as their best response; “stable disease (SD)”; and “primary progressors (PP)”—patients with progression of disease as their best response to ibrutinib. The primary objective of the study was to evaluate the real-world efficacy outcomes of ibrutinib in R/R MZL including response rates, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Secondary objectives included the evaluation of factors predictive of PP, PFS, and OS. See supplementary appendix for definitions and statistical analysis.

A total of 119 patients met the inclusion criteria. Sixty-nine patients achieved a disease response (ORR 58% with a CR rate of 17%), 35 (29%) had SD, and 15 (13%) had PP. Table 1 shows the baseline characteristics of the patient population. Among the 69 patients who achieved CR/PR, median DOR was 36.8 months (95% CI 25.5-NR) (Additional file 1: Fig. S1A). When stratified by CR or PR status (Additional file 1: Fig. S1B), median DOR was not reached (NR) (95% CI 32-NR) in patients who achieved CR compared to 26 months (95% CI 20.2-NR) in those achieving PR (p = 0.057). Median PFS and OS for the entire group (n = 119) were 29 months (Additional file 1: Fig. S2A) and 71.4 months (Additional file 1: Fig. S2B), respectively. The 1-year and 2-year PFS and OS rates were 66% and 55%, and 87% and 85%, respectively. When stratified by the ibrutinib line of therapy (second line vs. third line vs. fourth line and beyond), there was no difference in PFS (median PFS in similar order, 28.5 months vs. 28.2 months vs. 39.8 months, respectively, p = 0.89, Additional file 1: Fig. S3A) or OS (median OS in similar order, NR vs. 71.4 months vs. 44.5 months, respectively, p = 0.37, Additional file 1: Fig. S3B). Among the factors evaluated to determine the predictors of PFS and OS (see Additional file 1: Tables S1 and S2), complex cytogenetics portended inferior PFS (HR = 3.08, 95% CI 1.23–7.67, p = 0.02), while both complex cytogenetics (HR = 3.00, 95% CI 1.03–8.68, p = 0.04) and PP (HR = 13.94, 95% CI 5.17–37.62, p < 0.001) were associated with poor OS. Among the factors evaluated for association with PP (Table 2), only primary refractory disease (to first-line therapy) predicted a higher probability of PP to ibrutinib (RR = 3.77, 95% CI 1.15–12.33, p = 0.03). Lastly, the prior line of therapy (Additional file 1: Table S3) was not associated with differences in outcomes associated with ibrutinib therapy (Additional file 1: Figs. S4 and S5).

Table 1 Baseline characteristics
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Table 2 Modeling on risk of progression on ibrutinib
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In this multicenter retrospective study, we made several important observations. First, the ORR to ibrutinib was 58% with predominantly PRs (41%), which is in line with the results of the phase 2 registration trial [4, 5]. Second, the median DOR was 36.8 months and was longer in those achieving CR compared to PR (although not statistically significant). Third, patients with primary refractory disease had a significantly higher probability of progression on ibrutinib. Fourth, there was no difference in the PFS, or OS based on the number or type of prior therapies. This is in contrast to the data in mantle cell lymphoma, wherein the greatest benefit from ibrutinib was noted in patients receiving ibrutinib in earlier lines of therapy (especially second-line therapy) [6]. Fifth, the presence of complex cytogenetics was predictive of inferior PFS and OS.

The ORR and DOR with ibrutinib in R/R MZL patients in our study were in line with the results of the phase 2 registration trial [4, 5]. The median PFS, however, was longer in the current study (29 months) compared to the previously published results (15.7 months) [5]. One plausible explanation could be the receipt of rituximab monotherapy prior to ibrutinib, which was higher in the current study (49% vs. 27% in the phase 2 trial), as the median PFS was 30.4 months in the recipients of rituximab monotherapy in the clinical trial [5]. Another possible explanation is that in clinical trials routine scans are performed at frequent intervals and radiologic but asymptomatic relapses are picked up. Scheduled surveillance scans are typically less frequent outside of a clinical trial, and as a result, asymptomatic progressions may not be identified until a patient experiences clinical evidence of progression, thus making the PFS appear longer.

We did not capture the information on the toxicity and dose modification of ibrutinib (dose interruption or discontinuation) in the current study. Other limitations include the lack of data on CD5, Ki-67 expression, and MYD88 mutation status precluding our ability to study the impact of these variables on response and survival.

In conclusion, in this first and the largest study to date to report the real-world outcomes of R/R MZL treated with ibrutinib, we show that patients with primary refractory disease and those with PP on ibrutinib are very high-risk subsets and need to be prioritized for experimental and cellular therapies.