What is the efficacy of bendamustine combined with rituximab in the first-line treatment of extranodal marginal zone lymphoma?

Extranodal marginal zone lymphoma (EMZL) is a heterogeneous non-Hodgkin lymphoma that is usually diagnosed at an early stage and long-term localized to the site of origin, in patients with stage I EMZL at any site, including H.
pylori eradication In patients with gastric involvement after treatment failure, radiation therapy is the preferred approach
.

However, 20%-40% of patients with EMZL have advanced disease associated with poor prognosis
.

Treatment of patients with advanced disease remains controversial
.

The National Comprehensive Cancer Network (NCCN) guidelines list bendamustine in combination with rituximab (BR) as one of three preferred options for the treatment of EMZL
.

However, data supporting the application of this scheme in EMZL are limited
.

Therefore, larger observational studies are needed to provide more accurate data on the safety and efficacy of BR in treatment-naïve EMZL patients
.

Therefore, the researchers explored the efficacy and safety of BR in the first-line treatment of EMZL patients
.

Methods: The study identified 274 adult patients with EMZL receiving first-line BR from January 2008 to September 2020, allowing inclusion of patients who had received radiation, surgery, or H.
pylori eradication therapy
.

A total of 237 patients were included in the analysis
.

Findings 1.
Patient Baseline Characteristics The median age at diagnosis of the patients was 63 years (range: 21-85 years), and the female to male ratio was 1.
2:1
.

Most patients had an ECOG PS score of 0-1 (PS 0: 65%; PS 1: 31.
2%)
.

179 (75.
5%) patients had advanced (III-IV) disease; however, elevated LDH (19%; n=45) and B symptoms (17.
7%; n=42) were uncommon
.

Most patients had no bone marrow involvement (60.
8%; n=144) and had fewer than 4 sites of lymph node involvement (79.
7%; n=189)
.

Most patients had 1 extranodal disease site (54.
9%; n=130), followed by 2 sites (27.
4%; n=65) and 3 sites (12.
7%; n=30)
.

Common extranodal sites included lung (25.
3%; n=60), followed by stomach (17.
3%; n=41) and soft tissue (10.
1%; n=24)
.

Only 2 patients had H.
pylori-associated gastric EMZL (4.
4%), and both had experienced antibiotic treatment failure prior to receiving BR
.

MALT-IPI score risk was intermediate (1 risk factor) in 49.
8% of patients and high risk (≥2 risk factors) in 33.
3% (Table 1)
.

Table 1 Baseline characteristics of patients 2.
Treatment status The median time from diagnosis to BR treatment was 56 days (interquartile range, 31-98) (95% CI, 49-64), with data available among patients (n=181) For 6 cycles (range: 1-8), 48 patients (20.
3%) received rituximab maintenance therapy for a median duration of 16 months
.

Nine patients (3.
8%) received consolidation radiotherapy to the involved site
.

Treatment response was assessed using PET/CT in 140 patients (59%) and CT scan in the remaining patients
.

The overall response rate (ORR) for first-line BR was 93.
2%, the complete response (CR) rate was 81%, and the partial response (PR) rate was 12.
2%
.

Among the patients whose response was assessed by PET/CT, the ORR was 96.
5%, and the CR rate was 82.
9%; among the patients whose response was assessed by CT, the ORR was 92.
5%, and the CR rate was 81.
7%
.

Patients with localized disease (stages I-II) had higher CR rates compared with advanced (III-IV) patients (93% and 79%, respectively; P=0.
016)
.

In 180 patients with data, the incidence of infectious complications during BR treatment was 13%
.

Among these patients, 7 cases of herpes zoster reactivation (4%), 5 cases of pneumonia (3%) and influenza (3%) were observed
.

Among patients receiving rituximab maintenance therapy, neutropenia occurred in 3 patients (6.
2%), shingles reactivation in 1 patient (2%), and facial cellulitis (2%)
.

Eight patients (3.
4%) developed secondary malignancies after BR treatment, including one each of acute myeloid leukemia and one case of cutaneous squamous cell carcinoma
.

3.
Survival analysis 36 patients had disease progression and 18 died
.

With a median follow-up of 3.
21 years (range: 0-10.
75), the estimated 5-year PFS and OS rates were 80.
5% (95% CI, 73.
1%-86.
0%) and 89.
6% (95% CI, 83.
1%-93.
6%), respectively ) (Figure 1A-B)
.

The other 10 deaths were caused by head trauma, lung cancer, liver cirrhosis/hepatocellular carcinoma, respiratory failure, bladder cancer, acute myeloid leukemia, arrhythmia, and amyotrophic lateral sclerosis
.

There was no difference in PFS between patients who achieved CR or PR after BR treatment (HR: 0.
47; 95% CI, 0.
18-1.
27; P=0.
12)
.

Better PFS was not observed by number of BR cycles (P=0.
222), however, shorter OS was observed in patients treated with 1-3 cycles (P=0.
009)
.

Patients who received rituximab maintenance therapy after achieving CR or PR after BR showed longer PFS (5-year PFS rate of 94.
4% vs 81.
1%; P=0.
0121), while there was no difference in OS (P=0.
168) ) (Figure 1C-D)
.

No differences in PFS or OS were observed between gastric and other sites of EMZL patients (PFS: P=0.
885 and OS: P=0.
486) (Fig.
1E-F)
.

Furthermore, MALT-IPI scores did not predict PFS and OS (Fig.
1G–H)
.

Figure 2 Survival of EMZL patients treated with BR In univariate Cox regression analysis, the variables associated with shorter PFS were age ≥70 years (HR: 2.
07; 95% CI, 1.
03-4.
14; P=0.
040), B symptoms ( HR: 2.
56; 95%CI, 1.
25-5.
24; P=0.
01), did not achieve CR (HR: 5.
31; 95%CI, 2.
63-10.
73; P<0.
001), and maintained rituximab (HR=0.
18; 95% CI, 0.
04-0.
79; P=0.
023) was associated with longer PFS
.

Variables associated with shorter OS were not achieving CR (HR: 4.
67; 95% CI, 1.
71-12.
79; P=0.
003) and 1-3 cycles of BR treatment (HR: 5.
19; 95% CI, 1.
60-16.
90; P=0.
006) (Table 2)
.

In the multivariate Cox model, the presence of B symptoms was associated with shorter PFS and rituximab maintenance therapy was associated with longer PFS (HR: 0.
16; 95% CI, 0.
04-0.
71; P=0.
016), but does not affect OS (Table 3)
.

Table 2 Univariate Cox model analysis of PFS and OSTable 3 Multivariate Cox model analysis of PFS and OS Study conclusions BR regimen is a highly effective first-line treatment regimen in patients with EMZL that provides durable remission and overcomes known poor prognostic factors
.

This regimen is associated with the development of herpes zoster, so preventive treatment can be considered
.

Reference source: Juan Pablo Alderuccio, Luca Arcaini, Marcus P.
Watkins, et al.
An international analysis evaluating frontline bendamustine with rituximab in extranodal marginal zone lymphoma.
Blood Adv (2022) 6 (7): 2035–2044.
https:// doi.
org/10.
1182/bloodadvances.
2021006844.
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